{"gene":"PLG","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1970,"finding":"Plasminogen was purified from human plasma by affinity chromatography on L-lysine-substituted Sepharose, demonstrating that plasminogen binds specifically and with high affinity to lysine residues, enabling its isolation with >200-fold purification and a specific activity of 100 caseinolytic units/mg nitrogen.","method":"Affinity chromatography (lysine-Sepharose), caseinolytic activity assay, disc-gel electrophoresis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — foundational biochemical purification and activity assay, highly replicated","pmids":["5475635"],"is_preprint":false},{"year":1967,"finding":"Plasminogen is activated to plasmin by cleavage of a specific peptide bond, yielding a two-chain serine protease (heavy chain containing kringle domains, light chain containing the active site); the mechanism involves limited proteolysis by plasminogen activators.","method":"Biochemical peptide chain analysis, N-terminal sequencing, enzyme kinetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical characterization of activation mechanism, foundational and widely replicated","pmids":["4226004"],"is_preprint":false},{"year":1978,"finding":"Hereditary abnormal plasminogen (reduced enzymatic activity with normal antigen levels) was identified in a patient with recurrent thrombosis and their kindred, demonstrating that PLG mutations cause thrombotic disease through a loss-of-function mechanism affecting catalytic activity.","method":"Plasminogen activity assay, antigen quantitation, isoelectric focusing gel electrophoresis, active site titration, family segregation analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods with genetic segregation analysis","pmids":["659588"],"is_preprint":false},{"year":1976,"finding":"Alpha2-plasmin inhibitor (alpha2-antiplasmin) was isolated from human plasma and shown to instantaneously inhibit plasmin by forming a covalent 1:1 molar complex with the light chain (active site) of plasmin, thereby blocking activator-induced clot lysis; it does not inhibit urokinase at the same rate.","method":"Protein purification, SDS-PAGE, immunoelectrophoresis, enzyme inhibition kinetics, cross-linking/complex formation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted inhibition with defined stoichiometry and identified interaction domain, widely replicated","pmids":["134998"],"is_preprint":false},{"year":1985,"finding":"Platelets bind plasminogen at physiological concentrations via high-affinity lysine-dependent sites (Kd ~2.6 µM on thrombin-stimulated platelets, ~190,000 molecules/cell), and cell surface-bound plasminogen is preferentially activated to plasmin by tissue plasminogen activator, urokinase, or streptokinase, localizing fibrinolytic activity to the platelet surface.","method":"Radioiodinated ligand binding assay, Scatchard analysis, omega-aminocarboxylic acid competition, gel analysis of plasmin generation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — quantitative binding assay with competitive inhibition and direct plasmin generation measurement","pmids":["3920216"],"is_preprint":false},{"year":1987,"finding":"The complete coding sequence of human plasminogen was determined from a full-length liver cDNA clone (2.7 kb insert), revealing the primary structure and correcting several previously reported amino acid residues.","method":"cDNA library screening, nucleotide sequencing","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — direct sequence determination of full-length PLG cDNA","pmids":["3030813"],"is_preprint":false},{"year":1991,"finding":"A novel carboxypeptidase B (pCPB) was isolated from human plasma by plasminogen-Sepharose affinity chromatography, demonstrating that it is a plasminogen-binding protein; when activated by trypsin it cleaves carboxypeptidase B substrates (hippuryl-Arg, hippuryl-Lys), suggesting a role in removing C-terminal lysines from partially degraded fibrin to regulate plasminogen binding and fibrinolysis.","method":"Affinity chromatography, SDS-PAGE, N-terminal sequencing, cDNA cloning, trypsin activation, carboxypeptidase B substrate cleavage assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — protein isolation, cloning, and enzymatic characterization with defined substrates","pmids":["1939207"],"is_preprint":false},{"year":1994,"finding":"Angiostatin, a 38 kDa internal fragment of plasminogen containing kringle domains 1–4, was identified as a circulating angiogenesis inhibitor that specifically inhibits endothelial cell proliferation and potently blocks neovascularization and metastatic growth in vivo; intact plasminogen does not share this activity.","method":"Protein purification and sequencing from tumor-bearing mouse serum/urine, endothelial cell proliferation assay, in vivo metastasis suppression model, systemic angiostatin administration","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — protein isolated, sequenced, and tested in both in vitro and in vivo functional assays","pmids":["7525077"],"is_preprint":false},{"year":1996,"finding":"Individual kringle domains of angiostatin were characterized: kringle 1 (ED50 ~320 nM) and kringle 3 (ED50 ~460 nM) exhibit the most potent anti-proliferative activity against endothelial cells, kringle 2 shows moderate activity, and kringle 4 is ineffective; lysine-binding capability does not correlate with anti-endothelial potency, but proper kringle folding is essential.","method":"Recombinant kringle domain expression, endothelial cell proliferation assay, bFGF-stimulated growth inhibition, structure–activity analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic structure-function analysis with recombinant domains and quantitative bioassay","pmids":["8910613"],"is_preprint":false},{"year":1997,"finding":"The urokinase-plasmin system controls type IV collagenase (MMP-2 and MMP-9) activity through a cell-surface mechanism: binding of uPA and plasminogen to the cell surface leads to gelatinase activation; inhibition of cell-surface uPA or plasminogen binding blocks gelatinase activation; in soluble phase plasmin degrades both gelatinases, providing a regulatory switch between activation and inactivation.","method":"Cell surface binding inhibition, MMP zymography, gelatinase activation assays, soluble phase proteolysis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal assays establishing cell-surface mechanism with epistasis logic","pmids":["9171346"],"is_preprint":false},{"year":1997,"finding":"Matrix metalloproteinases MMP-7 (matrilysin) and MMP-9 (gelatinase B) cleave human plasminogen to generate angiostatin-like fragments (~58 kDa, ~42 kDa, ~38 kDa); both enzymes cut N-terminal to kringle domain 5, with MMP-7 and MMP-9 having closely spaced but distinct cleavage sites between kringle 4 and 5, identifying MMPs as angiostatin-converting enzymes.","method":"In vitro proteolysis, N-terminal sequencing, SDS-PAGE fragment analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with cleavage site determination by N-terminal sequencing","pmids":["9360944"],"is_preprint":false},{"year":1998,"finding":"Streptococcal surface enolase (SEN/alpha-enolase), a 45 kDa glycolytic enzyme displayed on the surface of group A streptococci, binds plasmin(ogen) with high affinity through its C-terminal lysine residue and an additional N-terminal region; SEN-bound plasmin retains proteolytic activity and is protected from inhibition, implicating this interaction in streptococcal tissue invasion.","method":"Protein purification and identification, immunoelectron microscopy, dose-dependent activity assay, competitive plasminogen binding inhibition, cross-linking studies with intact streptococci, monoclonal antibody blocking","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods identifying binding mechanism and functional protection of plasmin activity","pmids":["9603964"],"is_preprint":false},{"year":1999,"finding":"Angiostatin binds to the alpha/beta subunits of ATP synthase on the surface of human endothelial cells (55 kDa binding partner), distinct from the plasminogen binding site (annexin II, 44 kDa); angiostatin's antiproliferative effect on endothelial cells is inhibited by up to 90% by anti-alpha-subunit ATP synthase antibody, identifying cell-surface ATP synthase as the functional angiostatin receptor.","method":"Ligand blot analysis, amino-terminal sequencing, peptide mass fingerprinting, flow cytometry, immunofluorescence, binding studies with recombinant ATP synthase subunit, antibody inhibition of antiproliferative effect","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — protein identified by multiple methods, functional antibody blockade confirmed mechanism","pmids":["10077593"],"is_preprint":false},{"year":2001,"finding":"Angiomotin, a novel protein identified by yeast two-hybrid screening with angiostatin kringle domains 1–4, localizes to the leading edge of migrating endothelial cells and mediates angiostatin's inhibitory effects on endothelial cell migration and tube formation; expression of angiomotin increases basal migration but renders cells susceptible to angiostatin inhibition.","method":"Yeast two-hybrid screening, fluorescent angiostatin internalization assay, immunofluorescence localization, endothelial migration and tube formation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid with functional validation in cell migration and tube formation assays","pmids":["11257124"],"is_preprint":false},{"year":2001,"finding":"Plasmin cleaves the proforms of NGF and BDNF extracellularly; proNGF acts as a high-affinity ligand for p75NTR preferentially inducing apoptosis rather than TrkA-mediated survival, revealing that PLG-dependent extracellular proteolysis switches neurotrophin signaling from survival to cell death.","method":"In vitro plasmin cleavage of proneurotrophins, receptor binding assays (p75NTR vs TrkA), neuronal apoptosis assays, TrkA phosphorylation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of proteolytic cleavage combined with receptor-specific functional assays","pmids":["11729324"],"is_preprint":false},{"year":2004,"finding":"Human plasminogen is a critical host pathogenicity factor for group A streptococcal infection; streptokinase specifically activates human but not mouse plasminogen, and transgenic expression of human plasminogen in mice dramatically increased streptococcal mortality in a streptokinase-dependent manner, establishing the PLG-streptokinase axis as the primary determinant of host species specificity for streptococcal infection.","method":"Transgenic mouse model expressing human plasminogen, bacterial infection challenge, genetic deletion of streptokinase, survival analysis with mechanistic comparison","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in transgenic/knockout mouse model with clear mechanistic conclusion","pmids":["15333838"],"is_preprint":false},{"year":2009,"finding":"Plg-RKT (C9orf46 homolog) was identified as a novel integral membrane plasminogen receptor that exposes a C-terminal lysine on the cell surface; it is induced during monocyte differentiation, co-localizes with uPAR on the cell surface, interacts directly with tissue plasminogen activator, and markedly promotes cell surface plasminogen activation.","method":"MudPIT proteomics with carboxypeptidase B treatment, flow cytometry, co-localization studies, plasminogen activation assay, database mining for expression","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — discovery by quantitative proteomics plus functional plasminogen activation assay and co-localization","pmids":["19897580"],"is_preprint":false},{"year":2010,"finding":"Extracellular hsp90alpha, secreted via exosomes by invasive cancer cells, interacts with tissue plasminogen activator (tPA) and, together with annexin II (also present in exosomes), activates plasmin; this extracellular hsp90alpha-tPA complex promotes plasmin-dependent cancer cell motility.","method":"Mass spectrometry, co-immunoprecipitation, plasmin activation assay, migration assay with inhibitors, exosome isolation and characterization","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and functional assay in single study; plasmin activation confirmed by direct assay","pmids":["20553606"],"is_preprint":false},{"year":2011,"finding":"Plg-RKT plays a key role in macrophage invasion, chemotactic migration, and in vivo recruitment: anti-Plg-RKT antibody inhibited uPA-mediated plasminogen activation (by 39%), Matrigel invasion in response to MCP-1 (by 54%), chemotactic migration (by 64%), and peritoneal macrophage recruitment in thioglycollate-induced peritonitis (by 58%); anti-Plg-RKT antibody had no additional effect in plasminogen-null mice, establishing plasminogen-dependence.","method":"Anti-Plg-RKT mAb blockade, Matrigel invasion assay, chemotaxis assay, mouse peritonitis model, plasminogen-null mice comparison, pro-MMP-9 activation measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays with genetic (plasminogen-null) epistasis confirmation","pmids":["21940822"],"is_preprint":false},{"year":2011,"finding":"Plg-RKT is expressed on the surface of catecholaminergic cells (chromaffin cells, PC12 cells); it co-immunoprecipitates with uPAR, is an integral plasma membrane protein, and its overexpression markedly enhances plasminogen activation; cells overexpressing Plg-RKT show 51% reduction in nicotine-evoked norepinephrine release, while antibody blockade of endogenous Plg-RKT increases norepinephrine release, establishing Plg-RKT as a regulator of catecholamine secretion through plasmin-mediated proteolysis of prohormones.","method":"Stable overexpression, antibody blockade, co-immunoprecipitation with uPAR, FACS analysis, phase partitioning, plasminogen activation assay, [3H]norepinephrine secretion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional evidence (overexpression + antibody blockade) with co-IP and direct secretion assay","pmids":["21795689"],"is_preprint":false},{"year":2016,"finding":"Genetic deletion of Plg-RKT in mice demonstrated that Plg-RKT is required for plasminogen binding to macrophages and for macrophage migration in vivo in experimental peritonitis; Plg-RKT deficiency also causes complete failure of lactation (all offspring of Plg-RKT−/− females die within 2 days of birth) and affects female but not male growth rates.","method":"Homologous recombination knockout mice, macrophage plasminogen binding assay, peritonitis recruitment model, lactation phenotype assessment","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with quantitative plasminogen binding and in vivo functional phenotype","pmids":["27714956"],"is_preprint":false},{"year":2017,"finding":"A heterozygous missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of PLG was identified in patients with hereditary angioedema with normal C1-INH, establishing a novel gain-of-function PLG mutation as a cause of hereditary angioedema through autosomal dominant inheritance.","method":"Whole-exome sequencing, Sanger sequencing, family segregation analysis, clinical phenotyping","journal":"Allergy","confidence":"High","confidence_rationale":"Tier 2 — genetic identification in multiple independent families with clear autosomal dominant segregation","pmids":["28795768"],"is_preprint":false},{"year":2018,"finding":"Plg-RKT is essential for mammary lobuloalveolar development and lactation: Plg-RKT−/− mice show blocked lobuloalveolar development due to hypertrophic fibrotic stroma, massive fibrin accumulation in alveoli/ducts, macrophage infiltration, 12-fold downregulation of EGF, absent epithelial cell proliferation, downregulation of pro-survival protein Mcl-1, and increased apoptosis; fibrinogen heterozygosity reduced fibrin accumulation but did not rescue lobuloalveolar defects, indicating plasminogen-independent mechanisms also contribute.","method":"Knockout mouse mammary gland analysis, immunohistochemistry for fibrin/macrophages/proliferation/apoptosis, transcriptional profiling, fibrinogen genetic reduction (compound knockout)","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with compound knockouts, multiple molecular readouts establishing mechanism","pmids":["29495105"],"is_preprint":false},{"year":2019,"finding":"Plasminogen and plasmin promote macrophage M2-like polarization and efferocytosis through transient STAT3 phosphorylation: in vitro, Plg/plasmin increased CD206/Arginase-1 and IL-10/TGF-β while suppressing LPS/IFN-induced M1 markers; in vivo, Plg−/− and Plg-RKT−/− mice showed increased M1-like macrophages, decreased CCL2, defective IL-4-induced M2 polarization, and reduced phagocytosis of apoptotic neutrophils.","method":"Murine pleurisy model, bone marrow-derived macrophage polarization assays, STAT3 phosphorylation western blot, flow cytometry (M1/M2 markers), efferocytosis assay in vivo and in vitro","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout models combined with in vitro mechanistic signaling assays in multiple cell types","pmids":["31316511"],"is_preprint":false},{"year":2019,"finding":"Plg-RKT is differentially expressed on proinflammatory monocyte/macrophage subsets (CD14++CD16+ human monocytes and Ly6Chigh mouse monocytes show highest expression); directional migration of proinflammatory monocytes is plasmin-dependent and abolished by anti-Plg-RKT mAb, ε-aminocaproic acid, aprotinin, and the aminoterminal fragment of uPA; Plg-RKT−/− mice show significantly less Ly6Chigh monocyte recruitment in peritonitis.","method":"Flow cytometry for Plg-RKT expression on monocyte subsets, plasminogen binding assay, directional migration assay with multiple inhibitors, in vivo peritonitis model in Plg-RKT−/− mice, immunohistochemistry in human carotid plaques","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple inhibitor strategies + genetic knockout with in vivo and in vitro concordant results","pmids":["31221672"],"is_preprint":false},{"year":2020,"finding":"Plg-RKT regulates cutaneous wound healing through plasminogen-dependent fibrinolysis and myeloid cell-mediated inflammation: Plg-RKT−/− mice show delayed wound closure during the proliferation phase, dysregulated cytokine expression, and impaired fibrin clearance; genetic reduction of fibrinogen levels by 50% completely abrogated the wound healing delay, and Plg-RKT deletion specifically in keratinocytes paradoxically accelerated healing with upregulation of filaggrin and caspase 14.","method":"Standardized burn wound model, conditional/constitutive Plg-RKT knockout mice (myeloid- and keratinocyte-specific), fibrin clearance measurement, fibrinogen compound knockouts, transcriptional profiling, cytokine quantitation","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional knockouts with genetic epistasis (fibrinogen reduction) establishing mechanistic pathway","pmids":["33311441"],"is_preprint":false},{"year":2021,"finding":"Plg-RKT on activated human and murine platelets retains platelet-derived plasminogen (secreted from alpha-granules) on the platelet membrane via a lysine-dependent mechanism; Plg-RKT co-localizes with platelet-derived plasminogen on activated platelet membranes; Plg-RKT−/− platelets show significantly attenuated plasminogen membrane exposure after activation; platelet-membrane-retained plasminogen drives local fibrinolysis by enhancing cell surface plasminogen activation.","method":"Western blotting of platelet membrane fractions, confocal microscopy, flow cytometry, ε-aminocaproic acid competition, fluorescent plasminogen-deficient clot lysis assay, turbidimetric clot lysis assay, Plg-RKT−/− mouse platelets","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including genetic knockout validation and direct fibrinolysis assay","pmids":["32842150"],"is_preprint":false},{"year":2021,"finding":"PLG silencing in HBV-positive hepatocellular carcinoma cells promoted apoptosis in vitro and suppressed tumor xenograft growth in vivo by inhibiting HBV replication; mechanistically, PLG activates SRC (a downstream target), which promotes Hippo pathway signaling to support HBV-HCC cell survival.","method":"siRNA knockdown, flow cytometry for apoptosis (TUNEL), subcutaneous xenograft model, qRT-PCR, western blot, KEGG/GO pathway analysis","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3–4 — bioinformatics-driven, single-lab study with limited mechanistic validation of PLG-SRC-Hippo axis","pmids":["33594307"],"is_preprint":false},{"year":2021,"finding":"Plg-RKT regulates adipose function and metabolic homeostasis: Plg-RKT is highly expressed in human and mouse adipose tissue and markedly upregulated during adipogenesis; Plg-RKT−/− mice on high-fat diet develop increased adipose and hepatic inflammation, macrophage/T-cell accumulation, fibrosis, hepatic steatosis, and insulin resistance; Plg-RKT regulates PPARγ and other adipogenic molecule expression, suggesting a novel role in the adipogenic transcriptional program.","method":"Immunofluorescence of human/mouse adipose tissue, high-fat diet mouse model, Plg-RKT−/− mice, 3T3-L1 and primary preadipocyte differentiation assays, insulin signaling western blot, RT-PCR for PPARγ","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with multiple metabolic readouts, but adipogenic mechanism requires further validation","pmids":["34897983"],"is_preprint":false},{"year":2023,"finding":"Plg-RKT is highly expressed by scar-associated macrophages (SAMs) in fibrotic liver; PLG treatment transforms bone-marrow-derived macrophages into SAMs expressing pro-fibrotic genes, an effect blocked by Plg-RKT knockdown; selective in vivo knockdown of Plg-RKT in intrahepatic macrophages using siRNA-GeRPs reduced SAM numbers and alleviated BDL- and CCl4-induced liver fibrosis.","method":"Single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), siRNA-GeRPs macrophage-selective knockdown, bone marrow-derived macrophage treatment assays, BDL and CCl4 mouse liver fibrosis models","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 — selective in vivo knockdown with in vitro mechanistic rescue, multiple fibrosis models","pmids":["37207518"],"is_preprint":false},{"year":2024,"finding":"Liver-secreted plasminogen signals directly to muscle satellite cells (via Plg-RKT/ERK kinase) to promote their proliferation during caloric restriction (CR); knockdown of circulating plasminogen prevents CR-induced satellite cell expansion; loss of Plg-RKT is also sufficient to prevent CR-related satellite cell expansion; these findings were replicated in human CALERIE trial participants.","method":"MetRSL274G transgenic mouse proteomics to identify liver-secreted factors, plasminogen knockdown (circulating), Plg-RKT knockout mice, satellite cell isolation and counting, ERK phosphorylation assay, human CALERIE trial analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models (knockdown + knockout) with defined Plg-RKT/ERK signaling axis and human replication","pmids":["38442019"],"is_preprint":false},{"year":2025,"finding":"In renal cell carcinoma, FABP1+ tumor cells signal to endothelial cells via the PLG-PLAT (tissue plasminogen activator) axis to promote plasmin-related tumor angiogenesis; spatial transcriptomics showed co-localization of FABP1+ tumors with PLAT+ endothelial cells, and receptor-ligand interaction analysis confirmed PLG-PLAT as a functional signaling axis between tumor and endothelial compartments.","method":"Single-cell RNA sequencing, spatial transcriptomics, receptor-ligand interaction analysis, preclinical tumor models, FABP1-PLG-PLAT axis functional experiments","journal":"Molecular cancer","confidence":"Low","confidence_rationale":"Tier 3 — computational interaction inference with limited direct mechanistic validation of the PLG-PLAT axis","pmids":["40518526"],"is_preprint":false},{"year":2010,"finding":"Three novel PLG gene mutations (C166Y, Y264S, IVS10-7T/G) were identified in patients with severe hypoplasminogenemia, a multisystemic disorder causing deficient extravascular fibrinolysis manifesting as ligneous conjunctivitis, periodontitis, hydrocephalus, and other mucosal membrane abnormalities; molecular genetic analysis of 23 cases confirmed that homozygous or compound-heterozygous PLG mutations underlie the clinical phenotype.","method":"Sanger sequencing, molecular genetic analysis, clinical phenotyping","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — genetic identification of novel loss-of-function mutations with clear phenotypic consequence, though mechanism is by inference from known PLG biology","pmids":["21174000"],"is_preprint":false}],"current_model":"Plasminogen (PLG) is the zymogen of the broad-spectrum serine protease plasmin, activated by limited proteolysis (cleavage between kringle and serine-protease domains) by tissue-type or urokinase-type plasminogen activators; plasminogen binds to cell surfaces via high-affinity interactions with C-terminal lysine residues on proteins including the transmembrane receptor Plg-RKT, annexin II, and alpha-enolase, where activation to plasmin is markedly enhanced and the resulting proteolytic activity is focused on fibrinolysis, extracellular matrix remodeling (through MMP activation), prohormone processing (generating catecholamine-regulatory peptides), proneurotrophin cleavage (switching p75NTR/TrkA signaling balance), and macrophage/monocyte recruitment and polarization; internal PLG kringle fragments (angiostatin, kringles 1–4) act as potent endothelial cell antiproliferative agents by binding ATP synthase and angiomotin on the endothelial surface; loss-of-function PLG mutations cause hypoplasminogenemia with defective mucosal wound healing, while gain-of-function kringle mutations cause hereditary angioedema; the dedicated transmembrane receptor Plg-RKT co-localizes with uPAR to orchestrate cell-surface plasminogen activation and is required for macrophage migration, mammary lobuloalveolar development and lactation, wound healing, resolution of inflammation, satellite cell expansion during caloric restriction, and metabolic homeostasis."},"narrative":{"teleology":[{"year":1967,"claim":"Resolving how an inactive zymogen becomes an active protease, biochemical analysis showed plasminogen is converted to the two-chain serine protease plasmin by limited proteolysis at a specific peptide bond, establishing the fundamental activation mechanism.","evidence":"Peptide chain analysis, N-terminal sequencing, and enzyme kinetics on purified plasminogen/plasmin","pmids":["4226004"],"confidence":"High","gaps":["Activator identity and specificity not yet defined","Structural basis of kringle domain–active site chain association unknown"]},{"year":1970,"claim":"Demonstrating the molecular basis of plasminogen's surface-binding capacity, affinity chromatography on lysine-Sepharose showed that plasminogen binds specifically to lysine residues, enabling its efficient purification and predicting lysine-dependent receptor interactions.","evidence":"Lysine-Sepharose affinity chromatography with caseinolytic activity assay","pmids":["5475635"],"confidence":"High","gaps":["Identity of physiological cell-surface lysine-bearing receptors unknown","Contribution of individual kringle domains to lysine binding not resolved"]},{"year":1976,"claim":"Identifying the principal physiological brake on plasmin, alpha2-antiplasmin was shown to form an instantaneous 1:1 stoichiometric complex with the plasmin active site, establishing the primary mechanism of plasmin inactivation in plasma.","evidence":"Protein purification, SDS-PAGE, and enzyme inhibition kinetics demonstrating covalent complex with plasmin light chain","pmids":["134998"],"confidence":"High","gaps":["Rate constants for inhibition of cell-surface-bound versus free plasmin not compared","Mechanism of fibrin-mediated protection from inhibition not defined"]},{"year":1978,"claim":"Linking PLG to human disease, identification of hereditary dysfunctional plasminogen (normal antigen, reduced activity) in a family with recurrent thrombosis demonstrated that PLG loss-of-function mutations cause thrombophilia.","evidence":"Plasminogen activity assay, antigen quantitation, active site titration, and family segregation","pmids":["659588"],"confidence":"High","gaps":["Molecular identity of the mutation not determined","Prevalence and spectrum of PLG mutations in thrombophilia unclear"]},{"year":1985,"claim":"Establishing that cell surfaces are privileged sites for plasmin generation, platelets were shown to bind plasminogen at high capacity via lysine-dependent sites and to preferentially support its activation by tPA, urokinase, and streptokinase.","evidence":"Radioiodinated ligand binding, Scatchard analysis, and cell-surface plasmin generation assay on thrombin-stimulated platelets","pmids":["3920216"],"confidence":"High","gaps":["Molecular identity of platelet plasminogen receptors not determined","Relative contribution of platelet- versus fibrin-surface plasmin to clot lysis unknown"]},{"year":1994,"claim":"Revealing a cryptic anti-angiogenic function within the plasminogen molecule, angiostatin (kringles 1–4) was identified as a circulating inhibitor of endothelial proliferation and metastatic neovascularization, distinct from any activity of intact plasminogen.","evidence":"Purification from tumor-bearing mouse serum, N-terminal sequencing, endothelial proliferation assay, and in vivo metastasis suppression","pmids":["7525077"],"confidence":"High","gaps":["Physiological protease(s) generating angiostatin in vivo not identified","Receptor mediating anti-proliferative activity unknown"]},{"year":1997,"claim":"Connecting plasminogen to matrix metalloproteinase cascades and angiostatin generation, cell-surface uPA/plasminogen activation was shown to activate MMP-2 and MMP-9, while MMP-7 and MMP-9 were identified as angiostatin-converting enzymes that cleave plasminogen between kringles 4 and 5.","evidence":"Cell-surface binding inhibition, MMP zymography, in vitro proteolysis with N-terminal sequencing of cleavage products","pmids":["9171346","9360944"],"confidence":"High","gaps":["In vivo relevance of MMP-generated angiostatin versus other proteolytic pathways not established","Regulation of the MMP–plasminogen crosstalk in specific tissues unclear"]},{"year":1999,"claim":"Identifying the functional angiostatin receptor, cell-surface ATP synthase alpha/beta subunits on endothelial cells were shown to bind angiostatin, and antibody blockade of the alpha subunit abolished up to 90% of angiostatin's anti-proliferative effect.","evidence":"Ligand blot, N-terminal sequencing, peptide mass fingerprinting, flow cytometry, and antibody inhibition of proliferation","pmids":["10077593"],"confidence":"High","gaps":["Downstream signaling from surface ATP synthase engagement not characterized","Relative contribution of ATP synthase versus angiomotin to angiostatin effects in vivo unknown"]},{"year":2001,"claim":"Expanding plasminogen's biological reach beyond fibrinolysis, plasmin was shown to cleave proNGF and proBDNF extracellularly, converting them from p75NTR-selective pro-apoptotic ligands into TrkA-activating mature neurotrophins, and angiomotin was identified as a second angiostatin-binding mediator of endothelial migration inhibition.","evidence":"In vitro plasmin cleavage of proneurotrophins with receptor binding and apoptosis assays; yeast two-hybrid identification of angiomotin with migration and tube-formation assays","pmids":["11729324","11257124"],"confidence":"High","gaps":["In vivo requirement of plasmin for proneurotrophin processing not established by genetic models at this time","Relative contributions of angiomotin and ATP synthase to angiostatin signaling unresolved"]},{"year":2004,"claim":"Demonstrating plasminogen as a host susceptibility factor in infection, streptokinase-specific activation of human (but not mouse) plasminogen was shown to be the key determinant of group A streptococcal virulence, as transgenic expression of human PLG in mice dramatically increased mortality in a streptokinase-dependent manner.","evidence":"Transgenic human-PLG mouse infection model with streptokinase-deletion bacteria and survival analysis","pmids":["15333838"],"confidence":"High","gaps":["Whether pathogen-hijacked plasmin acts through fibrinolysis, matrix degradation, or immune evasion not dissected","Relevance to other plasminogen-activating pathogens not tested"]},{"year":2009,"claim":"Identifying the dedicated cell-surface receptor that orchestrates plasminogen activation, Plg-RKT was discovered as an integral membrane protein exposing a C-terminal lysine, co-localizing with uPAR, and markedly enhancing tPA-dependent cell-surface plasminogen activation.","evidence":"MudPIT proteomics with carboxypeptidase B treatment, flow cytometry, co-localization, and plasminogen activation assay","pmids":["19897580"],"confidence":"High","gaps":["In vivo requirement not yet demonstrated by genetic deletion","Structural basis of Plg-RKT–plasminogen interaction unknown"]},{"year":2010,"claim":"Defining the genetic basis of hypoplasminogenemia, novel PLG mutations (C166Y, Y264S, IVS10-7T/G) in homozygous or compound-heterozygous states were confirmed to cause ligneous conjunctivitis, periodontitis, hydrocephalus, and other mucosal fibrin-deposition phenotypes.","evidence":"Sanger sequencing and molecular genetic analysis of 23 patients with clinical phenotyping","pmids":["21174000"],"confidence":"Medium","gaps":["Functional characterization of individual mutations (e.g., folding, secretion, activation kinetics) not performed","Genotype–phenotype correlations for severity not established"]},{"year":2011,"claim":"Genetic and antibody-blockade experiments established that Plg-RKT is required for macrophage chemotactic migration, Matrigel invasion, and peritoneal recruitment in a strictly plasminogen-dependent manner, and additionally regulates catecholamine secretion by chromaffin cells through plasmin-mediated prohormone processing.","evidence":"Anti-Plg-RKT mAb blockade in migration/invasion/peritonitis assays; plasminogen-null mice epistasis; overexpression and antibody studies in chromaffin/PC12 cells with norepinephrine secretion measurement","pmids":["21940822","21795689"],"confidence":"High","gaps":["Plg-RKT genetic knockout phenotype not yet available at this time","Prohormone substrates of plasmin on chromaffin cells not fully identified"]},{"year":2016,"claim":"Genetic deletion of Plg-RKT confirmed its non-redundant role in macrophage plasminogen binding and migration in vivo, and revealed an unexpected requirement for lactation, as all pups from Plg-RKT−/− dams died within 48 hours of birth.","evidence":"Plg-RKT knockout mice with macrophage binding assay, peritonitis model, and lactation phenotyping","pmids":["27714956"],"confidence":"High","gaps":["Mechanism of lactation failure (fibrinolytic vs. non-fibrinolytic) not resolved","Plg-RKT contribution to other tissue-specific plasminogen functions unexplored"]},{"year":2017,"claim":"Identification of the K330E kringle 3 missense mutation in families with hereditary angioedema and normal C1-inhibitor established a gain-of-function PLG mechanism as a novel cause of this disease.","evidence":"Whole-exome sequencing, Sanger validation, and autosomal dominant segregation in multiple families","pmids":["28795768"],"confidence":"High","gaps":["Biochemical mechanism of K330E gain-of-function (e.g., enhanced activation, altered binding) not characterized","Therapeutic implications not tested"]},{"year":2018,"claim":"Dissecting the lactation failure mechanism, Plg-RKT−/− mammary glands showed blocked lobuloalveolar development with fibrotic stroma, massive fibrin deposition, macrophage infiltration, EGF downregulation, and increased apoptosis; however, fibrinogen heterozygosity did not rescue the phenotype, indicating contributions beyond fibrinolysis.","evidence":"Plg-RKT−/− and compound Plg-RKT−/−;Fib+/− knockout mammary gland analysis with IHC, proliferation, apoptosis, and transcriptional profiling","pmids":["29495105"],"confidence":"High","gaps":["Plasminogen-independent Plg-RKT functions in mammary development not molecularly defined","Whether EGF downregulation is cause or consequence not resolved"]},{"year":2019,"claim":"Mechanistic studies revealed that plasminogen and plasmin promote M2-like macrophage polarization and efferocytosis through STAT3 phosphorylation, and that Plg-RKT is selectively enriched on proinflammatory monocyte subsets whose directional migration is plasmin-dependent.","evidence":"Plg−/− and Plg-RKT−/− mouse pleurisy/peritonitis models, BMDM polarization with STAT3 western blot, flow cytometry for M1/M2 markers and Plg-RKT on monocyte subsets, multiple inhibitor strategies","pmids":["31316511","31221672"],"confidence":"High","gaps":["Direct STAT3 target genes mediating M2 polarization not identified","Whether Plg-RKT signals independently of plasmin generation in polarization is unknown"]},{"year":2020,"claim":"Cell-type-specific knockouts showed that Plg-RKT in myeloid cells promotes wound healing through fibrin clearance and cytokine regulation, while keratinocyte-specific Plg-RKT deletion paradoxically accelerated healing with filaggrin upregulation, revealing opposing tissue-specific roles.","evidence":"Conditional Plg-RKT knockout mice (myeloid and keratinocyte-specific), burn wound model, fibrinogen compound knockouts, cytokine and transcriptional profiling","pmids":["33311441"],"confidence":"High","gaps":["Mechanism of keratinocyte Plg-RKT function (filaggrin regulation) not molecularly defined","Whether findings generalize to other wound types unknown"]},{"year":2021,"claim":"Extending the Plg-RKT axis to platelets and new tissue contexts, activated platelets were shown to retain alpha-granule-secreted plasminogen on their surface via Plg-RKT to drive local fibrinolysis, while Plg-RKT−/− mice on high-fat diet developed adipose and hepatic inflammation, fibrosis, and insulin resistance with dysregulated PPARγ.","evidence":"Confocal microscopy, flow cytometry, and clot lysis assays on Plg-RKT−/− platelets; high-fat diet metabolic phenotyping with Plg-RKT−/− mice and adipocyte differentiation assays","pmids":["32842150","34897983"],"confidence":"High","gaps":["Mechanism linking Plg-RKT to PPARγ regulation requires validation","Whether platelet Plg-RKT is specifically required vs. other plasminogen receptors not tested"]},{"year":2023,"claim":"In liver fibrosis, Plg-RKT was identified as highly expressed on scar-associated macrophages, where plasminogen treatment drives SAM differentiation; selective Plg-RKT knockdown in intrahepatic macrophages reduced SAM numbers and alleviated fibrosis in two independent models.","evidence":"scRNA-seq, CyTOF, siRNA-GeRP-mediated macrophage-selective knockdown, BDL and CCl4 liver fibrosis models","pmids":["37207518"],"confidence":"High","gaps":["Plasmin-dependent versus plasmin-independent SAM differentiation mechanisms not dissected","Translational potential in human liver fibrosis not tested"]},{"year":2024,"claim":"Revealing a systemic endocrine role, liver-secreted plasminogen was shown to signal via Plg-RKT and ERK kinase on muscle satellite cells to promote their proliferation during caloric restriction, replicated in human CALERIE trial participants.","evidence":"MetRSL274G transgenic mouse liver secretome proteomics, plasminogen knockdown, Plg-RKT knockout, satellite cell quantification, ERK phosphorylation, human CALERIE cohort validation","pmids":["38442019"],"confidence":"High","gaps":["Whether plasmin generation is required or Plg-RKT signals upon plasminogen binding not resolved","Downstream ERK targets in satellite cells not identified"]},{"year":null,"claim":"Major unresolved questions include the structural basis of Plg-RKT–plasminogen interaction, the biochemical mechanism of the K330E gain-of-function mutation in hereditary angioedema, whether Plg-RKT possesses plasmin-independent signaling capacity, and the relative contributions of plasminogen's fibrinolytic versus non-fibrinolytic functions in tissue-specific contexts such as mammary development, neurotrophin processing, and metabolic homeostasis.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of Plg-RKT–plasminogen complex","K330E biochemical mechanism uncharacterized","Plasmin-independent Plg-RKT signaling not confirmed or excluded"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,9,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,7,15,30]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,16,26]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,3,4,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,23,24,29]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,21,32]}],"complexes":[],"partners":["PLAT","PLAU","SERPINF2","ANXA2","PLGRKT","ENO1","AMOT","ATP5F1A"],"other_free_text":[]},"mechanistic_narrative":"Plasminogen (PLG) is the circulating zymogen of plasmin, a broad-spectrum serine protease central to fibrinolysis, extracellular matrix remodeling, macrophage recruitment and polarization, proneurotrophin processing, prohormone cleavage, and angiogenesis regulation. Plasminogen is activated by tissue-type and urokinase-type plasminogen activators via limited proteolysis at the kringle–serine protease domain junction, a process markedly enhanced when plasminogen is bound to cell-surface receptors—principally Plg-RKT, annexin II, and alpha-enolase—through lysine-dependent interactions [PMID:5475635, PMID:19897580, PMID:9603964]; cell-surface plasmin in turn activates MMP-2/MMP-9 to drive matrix degradation, cleaves proneurotrophins to switch p75NTR/TrkA signaling balance, and promotes M2-like macrophage polarization via STAT3 phosphorylation [PMID:9171346, PMID:11729324, PMID:31316511]. Internal kringle 1–4 fragments (angiostatin), generated by MMP-mediated cleavage, inhibit endothelial cell proliferation and neovascularization by binding cell-surface ATP synthase and angiomotin [PMID:7525077, PMID:10077593, PMID:11257124]. Homozygous or compound-heterozygous loss-of-function PLG mutations cause hypoplasminogenemia with ligneous conjunctivitis and mucosal fibrin deposition, while a heterozygous gain-of-function kringle 3 mutation (K330E) causes hereditary angioedema [PMID:21174000, PMID:28795768]."},"prefetch_data":{"uniprot":{"accession":"P00747","full_name":"Plasminogen","aliases":[],"length_aa":810,"mass_kda":90.6,"function":"Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1, C4 and C5 (PubMed:6447255). Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo (Microbial infection) ENO/enoloase from parasite P.falciparum (strain NF54) interacts with PLG present in the mosquito blood meal to promote the invasion of the mosquito midgut by the parasite ookinete (PubMed:21949403). The catalytic active form, plasmin, is essential for the invasion of the mosquito midgut (PubMed:21949403) (Microbial infection) Binds to OspC on the surface of B.burgdorferi cells, possibly conferring an extracellular protease activity on the bacteria that allows it to traverse host tissue (Microbial infection) Interacts with dengue virus type 2 particles (PubMed:31726374). Enhances dengue virus type 2 infection in Aedes aegypti mosquito midgut by increasing midgut internalization, resulting in higher infection rates and viral dissemination in mosquitoes (PubMed:31726374)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P00747/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLG","classification":"Not Classified","n_dependent_lines":56,"n_total_lines":1208,"dependency_fraction":0.046357615894039736},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLG","total_profiled":1310},"omim":[{"mim_id":"619360","title":"ANGIOEDEMA, HEREDITARY, 4; HAE4","url":"https://www.omim.org/entry/619360"},{"mim_id":"618807","title":"LIPOPROTEIN(a) QUANTITATIVE TRAIT LOCUS; LPAQTL","url":"https://www.omim.org/entry/618807"},{"mim_id":"618444","title":"PLASMINOGEN RECEPTOR WITH C-TERMINAL LYSINE; PLGRKT","url":"https://www.omim.org/entry/618444"},{"mim_id":"613329","title":"PLASMINOGEN ACTIVATOR INHIBITOR-1 DEFICIENCY","url":"https://www.omim.org/entry/613329"},{"mim_id":"613254","title":"TUBEROUS SCLEROSIS 2; TSC2","url":"https://www.omim.org/entry/613254"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":2479.5}],"url":"https://www.proteinatlas.org/search/PLG"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P00747","domains":[{"cath_id":"3.50.4.10","chopping":"26-101","consensus_level":"medium","plddt":83.7429,"start":26,"end":101},{"cath_id":"2.40.20.10","chopping":"183-199_209-268","consensus_level":"medium","plddt":87.2191,"start":183,"end":268},{"cath_id":"2.40.20.10","chopping":"269-352","consensus_level":"medium","plddt":86.4592,"start":269,"end":352},{"cath_id":"2.40.20.10","chopping":"379-453","consensus_level":"medium","plddt":90.2653,"start":379,"end":453},{"cath_id":"2.40.20.10","chopping":"484-559","consensus_level":"medium","plddt":87.1779,"start":484,"end":559},{"cath_id":"2.40.10.10","chopping":"570-810","consensus_level":"medium","plddt":87.2954,"start":570,"end":810}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00747","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00747-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00747-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLG","jax_strain_url":"https://www.jax.org/strain/search?query=PLG"},"sequence":{"accession":"P00747","fasta_url":"https://rest.uniprot.org/uniprotkb/P00747.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00747/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00747"}},"corpus_meta":[{"pmid":"19897580","id":"PMC_19897580","title":"Proteomics-based discovery of a novel, structurally unique, and developmentally regulated plasminogen receptor, Plg-RKT, a major regulator of cell surface plasminogen activation.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19897580","citation_count":117,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16360956","id":"PMC_16360956","title":"Encapsulation of the immune potentiators MPL and RC529 in PLG microparticles enhances their potency.","date":"2005","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/16360956","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29258717","id":"PMC_29258717","title":"Tolerogenic Ag-PLG nanoparticles induce tregs to suppress activated diabetogenic CD4 and CD8 T cells.","date":"2017","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/29258717","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6113579","id":"PMC_6113579","title":"Effect of L-prolyl-L-leucyl-glycinamide (PLG) on neuroleptic-induced catalepsy and dopamine/neuroleptic receptor bindings.","date":"1981","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/6113579","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16099080","id":"PMC_16099080","title":"Enhanced mucosal and systemic immune response with intranasal immunization of mice with HIV peptides entrapped in PLG microparticles in combination with Ulex Europaeus-I lectin as M cell target.","date":"2005","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/16099080","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21940822","id":"PMC_21940822","title":"Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21940822","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8578845","id":"PMC_8578845","title":"Synthetic delivery system for tuberculosis vaccines: immunological evaluation of the M. tuberculosis 38 kDa protein entrapped in biodegradable PLG microparticles.","date":"1995","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/8578845","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9619791","id":"PMC_9619791","title":"Monitoring microviscosity and microacidity of the albumin microenvironment inside degrading microparticles from poly(lactide-co-glycolide) (PLG) or ABA-triblock polymers containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethyleneoxide) B blocks.","date":"1998","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/9619791","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10825551","id":"PMC_10825551","title":"Incorporation of protein in PLG-microspheres with retention of bioactivity.","date":"2000","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/10825551","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23432371","id":"PMC_23432371","title":"PLG scaffold delivered antigen-specific regulatory T cells induce systemic tolerance in autoimmune diabetes.","date":"2013","source":"Tissue engineering. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/23432371","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15364441","id":"PMC_15364441","title":"Intranasal immunisation with Toxoplasma gondii tachyzoite antigen encapsulated into PLG microspheres induces humoral and cell-mediated immunity in sheep.","date":"2004","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/15364441","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31316511","id":"PMC_31316511","title":"Plasminogen and the Plasminogen Receptor, Plg-RKT, Regulate Macrophage Phenotypic, and Functional Changes.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31316511","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2966760","id":"PMC_2966760","title":"Linkage between the loci for the Lp(a) lipoprotein (LP) and plasminogen (PLG).","date":"1988","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2966760","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21174000","id":"PMC_21174000","title":"Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity.","date":"2010","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/21174000","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17324456","id":"PMC_17324456","title":"Patterned PLG substrates for localized DNA delivery and directed neurite extension.","date":"2007","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/17324456","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26777909","id":"PMC_26777909","title":"Chlorogenic Acid Maintains Glucose Homeostasis through Modulating the Expression of SGLT-1, GLUT-2, and PLG in Different Intestinal Segments of Sprague-Dawley Rats Fed a High-Fat Diet.","date":"2015","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/26777909","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21458857","id":"PMC_21458857","title":"Permanent protection of PLG scaffold transplanted allogeneic islet grafts in diabetic mice treated with ECDI-fixed donor splenocyte infusions.","date":"2011","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/21458857","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30458362","id":"PMC_30458362","title":"Localized immune tolerance from FasL-functionalized PLG scaffolds.","date":"2018","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/30458362","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21127300","id":"PMC_21127300","title":"Genetic variation in LPAL2, LPA, and PLG predicts plasma lipoprotein(a) level and carotid artery disease risk.","date":"2010","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/21127300","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17455338","id":"PMC_17455338","title":"Macromolecule release from monodisperse PLG microspheres: control of release rates and investigation of release mechanism.","date":"2007","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17455338","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6590153","id":"PMC_6590153","title":"Linkage of plasma alpha-L-fucosidase (FUCA2) and the plasminogen (PLG) system.","date":"1984","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6590153","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16200615","id":"PMC_16200615","title":"An investigation of the factors controlling the adsorption of protein antigens to anionic PLG microparticles.","date":"2005","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16200615","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15648244","id":"PMC_15648244","title":"Adsorption of a novel recombinant glycoprotein from HIV (Env gp120dV2 SF162) to anionic PLG microparticles retains the structural integrity of the protein, whereas encapsulation in PLG microparticles does not.","date":"2004","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/15648244","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15095816","id":"PMC_15095816","title":"A novel injectable approach for cartilage formation in vivo using PLG microspheres.","date":"2004","source":"Annals of biomedical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/15095816","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24909237","id":"PMC_24909237","title":"Enhancing human islet transplantation by localized release of trophic factors from PLG scaffolds.","date":"2014","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/24909237","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23804269","id":"PMC_23804269","title":"Tolerance strategies employing antigen-coupled apoptotic cells and carboxylated PLG nanoparticles for the treatment of type 1 diabetes.","date":"2012","source":"The review of diabetic studies : RDS","url":"https://pubmed.ncbi.nlm.nih.gov/23804269","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15309815","id":"PMC_15309815","title":"Enhanced protective efficacy of a tuberculosis DNA vaccine by adsorption onto cationic PLG microparticles.","date":"2004","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/15309815","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17683059","id":"PMC_17683059","title":"The potency of the adjuvant, CpG oligos, is enhanced by encapsulation in PLG microparticles.","date":"2008","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17683059","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24529725","id":"PMC_24529725","title":"New insights into the role of Plg-RKT in macrophage recruitment.","date":"2014","source":"International review of cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24529725","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27714956","id":"PMC_27714956","title":"Deficiency of plasminogen receptor, Plg-RKT , causes defects in plasminogen binding and inflammatory macrophage recruitment in vivo.","date":"2016","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/27714956","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20206921","id":"PMC_20206921","title":"Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization.","date":"2010","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20206921","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12636163","id":"PMC_12636163","title":"The effect of CTAB concentration in cationic PLG microparticles on DNA adsorption and in vivo performance.","date":"2003","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/12636163","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9396063","id":"PMC_9396063","title":"Modulation of dopamine receptor agonist-induced rotational behavior in 6-OHDA-lesioned rats by a peptidomimetic analogue of Pro-Leu-Gly-NH2 (PLG).","date":"1997","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/9396063","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2863809","id":"PMC_2863809","title":"Mesolimbic and striatal dopamine receptor supersensitivity: prophylactic and reversal effects of L-prolyl-L-leucyl-glycinamide (PLG).","date":"1985","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/2863809","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1981396","id":"PMC_1981396","title":"Modulation of high-affinity CNS dopamine D2 receptor by L-pro-L-leu-glycinamide (PLG) analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide.","date":"1990","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/1981396","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23507728","id":"PMC_23507728","title":"Relationship of vaccine efficacy to the kinetics of DC and T-cell responses induced by PLG-based cancer vaccines.","date":"2011","source":"Biomatter","url":"https://pubmed.ncbi.nlm.nih.gov/23507728","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8439170","id":"PMC_8439170","title":"Isolation and purification of propionicin PLG-1, a bacteriocin produced by a strain of Propionibacterium thoenii.","date":"1993","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8439170","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18929408","id":"PMC_18929408","title":"Layered PLG scaffolds for in vivo plasmid delivery.","date":"2008","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/18929408","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25208887","id":"PMC_25208887","title":"Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/25208887","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16316681","id":"PMC_16316681","title":"Nerve growth factor expression by PLG-mediated lipofection.","date":"2005","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/16316681","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31221672","id":"PMC_31221672","title":"Differential expression of Plg-RKT and its effects on migration of proinflammatory monocyte and macrophage subsets.","date":"2019","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/31221672","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10528070","id":"PMC_10528070","title":"Induction of cytotoxic T-cell responses following oral immunization with synthetic peptides encapsulated in PLG microparticles.","date":"1999","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/10528070","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31077862","id":"PMC_31077862","title":"Optimizing PLG nanoparticle-peptide delivery platforms for transplantation tolerance using an allogeneic skin transplant model.","date":"2019","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/31077862","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23602363","id":"PMC_23602363","title":"A PLG/HAp composite scaffold for lentivirus delivery.","date":"2013","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/23602363","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21795689","id":"PMC_21795689","title":"The novel plasminogen receptor, plasminogen receptor(KT) (Plg-R(KT)), regulates catecholamine release.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21795689","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9493876","id":"PMC_9493876","title":"Protection against MPTP treatment by an analog of Pro-Leu-Gly-NH2 (PLG, MIF-1).","date":"1998","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/9493876","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18612205","id":"PMC_18612205","title":"LPA and PLG sequence variation and kringle IV-2 copy number in two populations.","date":"2008","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/18612205","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32662180","id":"PMC_32662180","title":"Functions of the plasminogen receptor Plg-RKT.","date":"2020","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/32662180","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19911425","id":"PMC_19911425","title":"Cationic surface modification of PLG nanoparticles offers sustained gene delivery to pulmonary epithelial cells.","date":"2010","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19911425","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33311441","id":"PMC_33311441","title":"The plasminogen receptor, Plg-RKT, plays a role in inflammation and fibrinolysis during cutaneous wound healing in mice.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33311441","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6298884","id":"PMC_6298884","title":"CNS putative L-prolyl-L-leucyl-glycinamide (PLG) receptors, brain and lymphocyte dopamine receptors.","date":"1982","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/6298884","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21704093","id":"PMC_21704093","title":"The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue.","date":"2011","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/21704093","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15588094","id":"PMC_15588094","title":"Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold.","date":"2004","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15588094","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32842150","id":"PMC_32842150","title":"Exposure of plasminogen and a novel plasminogen receptor, Plg-RKT, on activated human and murine platelets.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32842150","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2893360","id":"PMC_2893360","title":"Down-regulation of haloperidol-induced striatal dopamine receptor supersensitivity by active analogues of L-prolyl-L-leucyl-glycinamide (PLG).","date":"1987","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/2893360","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35104243","id":"PMC_35104243","title":"PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35104243","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23125524","id":"PMC_23125524","title":"The plasminogen receptor, Plg-R(KT), and macrophage function.","date":"2012","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23125524","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8814328","id":"PMC_8814328","title":"Mucosal immunization with a measles virus CTL epitope encapsulated in biodegradable PLG microparticles.","date":"1996","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/8814328","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16713035","id":"PMC_16713035","title":"Development of hepatitis B oral vaccine using B-cell epitope loaded PLG microparticles.","date":"2006","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/16713035","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9413098","id":"PMC_9413098","title":"The immune response to a model antigen associated with PLG microparticles prepared using different surfactants.","date":"1997","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/9413098","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18191308","id":"PMC_18191308","title":"Polylactide-co-glycolide (PLG) microparticles modify the immune response to DNA vaccination.","date":"2007","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/18191308","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9873642","id":"PMC_9873642","title":"Beta-analogs of PLG (L-prolyl-L-leucyl-glycinamide): ex-chiral pool syntheses and dopamine D2 receptor modulating effects.","date":"1998","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/9873642","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1644425","id":"PMC_1644425","title":"Serum protein polymorphisms in Arab Moslems and Druze of Israel: BF, F13B, AHSG, GC, PLG, PI, and TF.","date":"1992","source":"Human biology","url":"https://pubmed.ncbi.nlm.nih.gov/1644425","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10476867","id":"PMC_10476867","title":"Synthesis and dopamine receptor modulating activity of unsubstituted and substituted triproline analogues of L-prolyl-L-leucyl-glycinamide (PLG).","date":"1999","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/10476867","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24013414","id":"PMC_24013414","title":"Synthesis and allosteric modulation of the dopamine receptor by peptide analogs of L-prolyl-L-leucyl-glycinamide (PLG) modified in the L-proline or L-proline and L-leucine scaffolds.","date":"2013","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24013414","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29495105","id":"PMC_29495105","title":"The plasminogen receptor, Plg-RKT, is essential for mammary lobuloalveolar development and lactation.","date":"2018","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/29495105","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15962265","id":"PMC_15962265","title":"A novel osteotropic biomaterial OG-PLG: in vitro efficacy.","date":"2005","source":"Journal of biomedical materials research. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/15962265","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15981201","id":"PMC_15981201","title":"A novel osteotropic biomaterial OG-PLG: Synthesis and in vitro release.","date":"2005","source":"Journal of biomedical materials research. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/15981201","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20943208","id":"PMC_20943208","title":"In vivo electroporation enhances the potency of poly-lactide co-glycolide (PLG) plasmid DNA immunization.","date":"2010","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/20943208","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17724659","id":"PMC_17724659","title":"Characterization of antigens adsorbed to anionic PLG microparticles by XPS and TOF-SIMS.","date":"2008","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17724659","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1572657","id":"PMC_1572657","title":"Genetic mapping of three human homologues of murine t-complex genes localizes TCP10 to 6q27, 15 cM distal to TCP1 and PLG.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1572657","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27830864","id":"PMC_27830864","title":"Novel l-prolyl-l-leucylglycinamide (PLG) tripeptidomimetics based on a 2-azanorbornane scaffold as positive allosteric modulators of the D2R.","date":"2016","source":"Organic & biomolecular chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27830864","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6141616","id":"PMC_6141616","title":"Are the pharmacological effects of L-prolyl-L-leucyl-glycinamide (PLG) mediated through specific receptor mechanisms?","date":"1983","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/6141616","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37093347","id":"PMC_37093347","title":"Plasma exosomal protein PLG and SERPINA1 in colorectal cancer diagnosis and coagulation abnormalities.","date":"2023","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37093347","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27224856","id":"PMC_27224856","title":"The preparation and characterization of PLG nanoparticles with an entrapped synthetic TLR7 agonist and their preclinical evaluation as adjuvant for an adsorbed DTaP vaccine.","date":"2016","source":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","url":"https://pubmed.ncbi.nlm.nih.gov/27224856","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37207518","id":"PMC_37207518","title":"Single-cell RNA seq identifies Plg-RKT-PLG as signals inducing phenotypic transformation of scar-associated macrophage in liver fibrosis.","date":"2023","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37207518","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33594307","id":"PMC_33594307","title":"PLG inhibits Hippo signaling pathway through SRC in the hepatitis B virus-induced hepatocellular-carcinoma progression.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33594307","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18421399","id":"PMC_18421399","title":"Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics.","date":"2008","source":"Organic & biomolecular chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18421399","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18980172","id":"PMC_18980172","title":"Preparation, physiochemical characterization, and oral immunogenicity of Abeta(1-12), Abeta(29-40), and Abeta(1-42) loaded PLG microparticles formulations.","date":"2009","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18980172","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38442019","id":"PMC_38442019","title":"Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38442019","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19073244","id":"PMC_19073244","title":"Encapsulated zinc salt increases the diffusion of protein through PLG films.","date":"2008","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/19073244","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1783400","id":"PMC_1783400","title":"Linkage of plasminogen (PLG) and apolipoprotein(a) (LPA) in baboons.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1783400","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34897983","id":"PMC_34897983","title":"The plasminogen receptor Plg-RKT regulates adipose function and metabolic homeostasis.","date":"2021","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/34897983","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32929111","id":"PMC_32929111","title":"Multi-omic studies on missense PLG variants in families with otitis media.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32929111","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25281489","id":"PMC_25281489","title":"Root dentin anomaly and a PLG mutation.","date":"2014","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25281489","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12576095","id":"PMC_12576095","title":"PLG regulates hnRNP-L expression in the rat striatum and pre-frontal cortex: identification by ddPCR.","date":"2003","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/12576095","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35454092","id":"PMC_35454092","title":"Plg-RKT Expression in Human Breast Cancer Tissues.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35454092","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34943952","id":"PMC_34943952","title":"Tolerance Induced by Antigen-Loaded PLG Nanoparticles Affects the Phenotype and Trafficking of Transgenic CD4+ and CD8+ T Cells.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34943952","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6507385","id":"PMC_6507385","title":"Parentage testing using the serum protein plasminogen (PLG).","date":"1984","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/6507385","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15063041","id":"PMC_15063041","title":"Measuring the heterogeneity of protein loading in PLG microspheres using flow cytometry.","date":"2004","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/15063041","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36129033","id":"PMC_36129033","title":"Case-only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD-2353F22.1 implying the importance of periodontal wound healing for disease aetiology.","date":"2022","source":"Journal of clinical periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/36129033","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11319106","id":"PMC_11319106","title":"Detection of the bacteriocin propionicin PLG-1 with polyvalent anti-PLG-1 antiserum.","date":"2001","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11319106","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18516668","id":"PMC_18516668","title":"Enhanced immune response of DNA vaccine (VP1-pCDNA) adsorbed on cationic PLG for foot and mouth disease in guinea pigs.","date":"2008","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/18516668","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26360520","id":"PMC_26360520","title":"Ligneous membranitis in Scottish Terriers is associated with a single nucleotide polymorphism in the plasminogen (PLG) gene.","date":"2015","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26360520","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1299313","id":"PMC_1299313","title":"Genetic serum protein polymorphisms in Jordanian Arabs: a pilot study of the systems AHSG, BF, F XIII B, GC, PI, PLG and TF.","date":"1992","source":"Gene geography : a computerized bulletin on human gene frequencies","url":"https://pubmed.ncbi.nlm.nih.gov/1299313","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36556936","id":"PMC_36556936","title":"Distinct Expression Patterns of Genes Coding for Biological Response Modifiers Involved in Inflammatory Responses and Development of Fibrosis in Chronic Hepatitis C: Upregulation of SMAD-6 and MMP-8 and Downregulation of CAV-1, CTGF, CEBPB, PLG, TIMP-3, MMP-1, ITGA-1, ITGA-2 and LOX.","date":"2022","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/36556936","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31159064","id":"PMC_31159064","title":"Long-Term Storage Stability of the Bacteriocin Propionicin PLG-1 Produced by Propionibacterium thoenii and Potential as a Food Preservative †.","date":"1996","source":"Journal of food protection","url":"https://pubmed.ncbi.nlm.nih.gov/31159064","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19146495","id":"PMC_19146495","title":"Differential expression of plg genes from Penicillium griseoroseum: plg1 a pectinolytic gene is expressed in sucrose and yeast extract.","date":"2008","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19146495","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40518526","id":"PMC_40518526","title":"Single-cell multi-omics reveals that FABP1 + renal cell carcinoma drive tumor angiogenesis through the PLG-PLAT axis under fatty acid reprogramming.","date":"2025","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40518526","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37486929","id":"PMC_37486929","title":"MPL36, a major plasminogen (PLG) receptor in pathogenic Leptospira, has an essential role during infection.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/37486929","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7525077","id":"PMC_7525077","title":"Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.","date":"1994","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7525077","citation_count":2865,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"5475635","id":"PMC_5475635","title":"Plasminogen: purification from human plasma by affinity chromatography.","date":"1970","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/5475635","citation_count":2303,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11729324","id":"PMC_11729324","title":"Regulation of cell survival by secreted proneurotrophins.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11729324","citation_count":1336,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15207811","id":"PMC_15207811","title":"The PDGF family: four gene products form five dimeric isoforms.","date":"2004","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/15207811","citation_count":618,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9020112","id":"PMC_9020112","title":"Interactions of mast cell tryptase with thrombin receptors and PAR-2.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9020112","citation_count":510,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"134998","id":"PMC_134998","title":"Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis.","date":"1976","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/134998","citation_count":465,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9603964","id":"PMC_9603964","title":"alpha-enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9603964","citation_count":451,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10077593","id":"PMC_10077593","title":"Angiostatin binds ATP synthase on the surface of human endothelial cells.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10077593","citation_count":439,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"4226004","id":"PMC_4226004","title":"The peptide chains of human plasmin. Mechanism of activation of human plasminogen to plasmin.","date":"1967","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/4226004","citation_count":429,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9171346","id":"PMC_9171346","title":"Control of type IV collagenase activity by components of the urokinase-plasmin system: a regulatory mechanism with cell-bound reactants.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9171346","citation_count":362,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2745554","id":"PMC_2745554","title":"SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca+2-dependent binding to the extracellular matrix.","date":"1989","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2745554","citation_count":356,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9360944","id":"PMC_9360944","title":"Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9).","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9360944","citation_count":356,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8910613","id":"PMC_8910613","title":"Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8910613","citation_count":340,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15333838","id":"PMC_15333838","title":"Plasminogen is a critical host pathogenicity factor for group A streptococcal infection.","date":"2004","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15333838","citation_count":322,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1939207","id":"PMC_1939207","title":"Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1939207","citation_count":317,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11257124","id":"PMC_11257124","title":"Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11257124","citation_count":306,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3920216","id":"PMC_3920216","title":"Binding and activation of plasminogen on the platelet surface.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3920216","citation_count":281,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"659588","id":"PMC_659588","title":"Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis.","date":"1978","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/659588","citation_count":275,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20553606","id":"PMC_20553606","title":"Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation.","date":"2010","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20553606","citation_count":243,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14574404","id":"PMC_14574404","title":"The DNA sequence and analysis of human chromosome 6.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14574404","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19199708","id":"PMC_19199708","title":"Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).","date":"2009","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/19199708","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28795768","id":"PMC_28795768","title":"Hereditary angioedema with a mutation in the plasminogen gene.","date":"2017","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/28795768","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25037231","id":"PMC_25037231","title":"Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25037231","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3030813","id":"PMC_3030813","title":"Molecular cloning and characterization of a full-length cDNA clone for human plasminogen.","date":"1987","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/3030813","citation_count":199,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46352,"output_tokens":3916,"usd":0.098898},"stage2":{"model":"claude-opus-4-6","input_tokens":7311,"output_tokens":6536,"usd":0.299932},"total_usd":0.847366,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":59854,"output_tokens":9081,"usd":0.157888},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12593,"output_tokens":5232,"usd":0.290648}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Plg-RKT (C9orf46 homolog) was identified as a novel integral membrane plasminogen receptor that exposes a C-terminal lysine on the cell surface, co-localizes with uPAR, interacts directly with tissue plasminogen activator, and markedly promotes cell surface plasminogen activation on eukaryotic cells.\",\n      \"method\": \"Multidimensional protein identification technology (MudPIT proteomics), carboxypeptidase B treatment, co-immunoprecipitation, cell surface plasminogen activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including proteomics, biochemical assays, and functional plasminogen activation assays in a single study\",\n      \"pmids\": [\"19897580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plg-RKT promotes macrophage invasion through Matrigel, chemotactic migration, and peritoneal recruitment in thioglycollate-induced peritonitis via plasminogen-dependent pro-MMP-9 activation; anti-Plg-RKT antibody did not further reduce macrophage recruitment in plasminogen-null mice, demonstrating plasminogen-dependence.\",\n      \"method\": \"Anti-Plg-RKT monoclonal antibody blockade, Matrigel invasion assay, chemotaxis assay, mouse peritonitis model, plasminogen-null mice (genetic epistasis)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO epistasis combined with functional cellular assays and in vivo model, replicated across multiple readouts\",\n      \"pmids\": [\"21940822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plg-RKT is expressed on the surface of catecholaminergic cells, co-immunoprecipitates with uPAR, and functions as an integral plasma membrane protein to enhance plasminogen activation; overexpression of Plg-RKT markedly decreased nicotine-evoked norepinephrine release (by 51%), while antibody blockade increased norepinephrine release, linking cell-surface plasminogen activation to regulation of catecholamine secretion.\",\n      \"method\": \"GFP fusion localization, phase partitioning, co-immunoprecipitation with uPAR, FACS, stable overexpression, antibody blockade, [3H]norepinephrine secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (co-IP, functional secretion assay, overexpression, antibody blockade) in a single study\",\n      \"pmids\": [\"21795689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of Plg-RKT in mice (Plg-RKT-/- knockout) demonstrated that Plg-RKT is required for plasminogen binding to macrophages and for macrophage recruitment in experimental peritonitis in vivo; Plg-RKT-/- female mice also exhibit a lactation defect causing death of all offspring within 2 days of birth.\",\n      \"method\": \"Homologous recombination knockout mice, peritonitis model, plasminogen binding assay, survival/reproduction phenotyping\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined phenotypic readouts (plasminogen binding, macrophage recruitment, lactation)\",\n      \"pmids\": [\"27714956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Plasminogen (Plg) and plasmin (Pla) promote macrophage M2 polarization (increasing CD206/Arginase-1, IL-10, TGF-β) and suppress M1 markers via transient STAT3 phosphorylation; Plg-/- and Plg-RKT-/- macrophages show reduced IL-4- and IL-10-stimulated STAT3 phosphorylation and defective efferocytosis of apoptotic neutrophils in vivo and in vitro.\",\n      \"method\": \"Bone-marrow-derived macrophage cultures from Plg-/- and Plg-RKT-/- mice, STAT3 phosphorylation assay, flow cytometry, murine pleurisy model, efferocytosis assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mice with multiple orthogonal mechanistic readouts (signaling phosphorylation, cytokine profiling, efferocytosis) in vivo and in vitro\",\n      \"pmids\": [\"31316511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Proinflammatory CD14++CD16+ human monocytes and Ly6Chigh mouse monocytes express the highest levels of Plg-RKT, bind significantly more plasminogen, and their directional plasmin-dependent migration is abolished by anti-Plg-RKT mAb, ε-aminocaproic acid, aprotinin, and the aminoterminal fragment of uPA; in vivo Plg-RKT-/- mice show significantly reduced Ly6Chigh monocyte recruitment in peritonitis.\",\n      \"method\": \"Flow cytometry, anti-Plg-RKT antibody blockade, plasminogen binding assay, Transwell migration assay, in vivo peritonitis model with Plg-RKT-/- mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods combining antibody blockade, KO mice, and in vitro/in vivo migration assays\",\n      \"pmids\": [\"31221672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plg-RKT is essential for mammary lobuloalveolar development and lactogenesis; Plg-RKT-/- glands showed fibrin accumulation, hypertrophic fibrotic stroma, macrophage infiltration, 12-fold downregulation of EGF, absent epithelial cell proliferation, downregulation of Mcl-1, and epithelial apoptosis; reducing fibrinogen by heterozygosity decreased fibrin accumulation but did not rescue lobuloalveolar defects, indicating both fibrinolytic and fibrinolysis-independent mechanisms.\",\n      \"method\": \"Plg-RKT-/- knockout mice, histology, immunofluorescence, fibrinogen genetic reduction (digenic cross), transcriptional profiling, Ki67/TUNEL proliferation/apoptosis assays\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with multiple orthogonal mechanistic readouts and genetic epistasis (fibrinogen reduction)\",\n      \"pmids\": [\"29495105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plg-RKT regulates cutaneous wound healing: myeloid-specific Plg-RKT deletion delayed healing during proliferation phase with dysregulated cytokine expression, while keratinocyte-specific deletion accelerated healing with upregulation of filaggrin and caspase-14; fibrin clearance was impaired in Plg-RKT-/- wounds and genetic reduction of fibrinogen to 50% abrogated the wound healing delay and normalized cytokine expression, establishing fibrin accumulation as a key downstream effector.\",\n      \"method\": \"Cell-type-specific conditional KO mice, standardized burn wound model, fibrinogen genetic reduction (digenic cross), cytokine profiling, qPCR (filaggrin, caspase-14), fibrin clearance measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with genetic epistasis (fibrinogen reduction) and multiple mechanistic readouts\",\n      \"pmids\": [\"33311441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT is expressed on activated human and murine platelets; platelet-derived plasminogen is retained on the activated platelet membrane via a lysine-dependent mechanism involving Plg-RKT; Plg-RKT-/- platelets show significantly reduced plasminogen exposure after activation; platelet-derived plasminogen drives local fibrinolysis by enhancing cell-surface plasminogen activation.\",\n      \"method\": \"Western blotting of platelet membrane fractions, confocal microscopy, flow cytometry, ε-aminocaproic acid treatment, Plg-RKT-/- mice, fluorescent fibrinolysis assay, turbidimetric clot lysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (imaging, flow cytometry, KO mice, functional fibrinolysis assay) in a single study\",\n      \"pmids\": [\"32842150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT-/- mice fed a high-fat diet gained more weight, developed more hepatic steatosis, and were more insulin resistant/glucose intolerant than wild-type; mechanistically, Plg-RKT deficiency increased adipose tissue inflammation, macrophage and T-cell accumulation, adipose and hepatic fibrosis, and decreased insulin signaling; Plg-RKT regulated PPARγ expression and adipogenesis in 3T3-L1 and primary preadipocytes.\",\n      \"method\": \"Plg-RKT-/- knockout mice, high-fat diet model, glucose/insulin tolerance tests, adipose tissue histology, immunofluorescence, primary preadipocyte culture, 3T3-L1 differentiation assay, Western blotting for insulin signaling\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse metabolic phenotype with in vitro adipogenesis assay, but single-lab study\",\n      \"pmids\": [\"34897983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liver-secreted plasminogen mediates muscle satellite cell expansion during caloric restriction; knockdown of circulating plasminogen prevents satellite cell expansion during CR, and loss of Plg-RKT is also sufficient to prevent CR-related satellite cell expansion, consistent with direct plasminogen signaling through Plg-RKT/ERK kinase to promote satellite cell proliferation.\",\n      \"method\": \"MetRSL274G transgenic mouse for liver-secreted protein identification, in vivo plasminogen knockdown, Plg-RKT-/- mice, ERK signaling assay, satellite cell quantification; findings replicated in human CALERIE trial participants\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic loss-of-function models (knockdown + KO) with identified signaling pathway (ERK) and human translational replication\",\n      \"pmids\": [\"38442019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Plg-RKT is highly expressed by scar-associated macrophages (SAMs) in fibrotic liver; PLG-treated bone-marrow-derived macrophages transformed into SAMs with pro-fibrotic gene expression, and Plg-RKT knockdown blocked this PLG-induced transformation; selective macrophage Plg-RKT knockdown in vivo reduced SAM accumulation and alleviated liver fibrosis in BDL and CCl4 models.\",\n      \"method\": \"scRNA-seq, CyTOF, siRNA-GeRP macrophage-selective knockdown in vivo, in vitro BMM culture with PLG treatment, mouse liver fibrosis models (BDL, CCl4)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo selective knockdown combined with in vitro mechanistic studies and single-cell multi-omic validation\",\n      \"pmids\": [\"37207518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Genetic linkage analysis demonstrated that the LP locus (determining Lp(a) lipoprotein levels) is linked to the plasminogen (PLG) locus on chromosome 6q (peak lod score = 12.73), physically assigning both loci to the same chromosomal region.\",\n      \"method\": \"Family linkage analysis, lod score calculation\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic linkage mapping without direct mechanistic biochemical experiment, but highly significant lod score\",\n      \"pmids\": [\"2966760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plg-RKT functions as a transmembrane plasminogen receptor with both N- and C-terminal domains extracellular; its C-terminal lysine tethers plasminogen to cell surfaces; Plg-RKT physically associates with uPAR to promote plasminogen activation to plasmin; Plg-RKT is required for lactation through both plasminogen-dependent and plasminogen-independent mechanisms, and its functions are sex-dependent.\",\n      \"method\": \"Review synthesizing data from overexpression, genetic deletion (Plg-RKT-/- mice), co-immunoprecipitation with uPAR, plasminogen binding assays, fibrinogen genetic reduction epistasis\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — synthesis of multiple primary studies using KO mice, co-IP, and functional assays from the same research group, independently supported\",\n      \"pmids\": [\"32662180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLG (plasminogen) is the zymogen of the broad-spectrum serine protease plasmin; its activation is markedly enhanced when tethered to cell surfaces via specific receptors—most notably Plg-RKT, a unique integral membrane receptor exposing a C-terminal lysine that physically associates with uPAR to concentrate plasminogen activation, thereby enabling plasmin-dependent macrophage/monocyte recruitment and migration, efferocytosis, fibrinolysis, wound healing, mammary lobuloalveolar development, muscle satellite cell expansion during caloric restriction, adipose metabolic homeostasis, and macrophage polarization, with downstream signaling involving STAT3 and ERK pathways.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about canonical PLG (plasminogen gene/protein): KEEP\n- Papers about poly(lactide-co-glycolide) polymer (also abbreviated PLG): EXCLUDE (alias collision)\n- Papers about Pro-Leu-Gly-NH2 tripeptide (also abbreviated PLG/MIF-1): EXCLUDE (alias collision)\n- Papers about propionicin PLG-1 bacteriocin: EXCLUDE (alias collision)\n- Papers about Penicillium plg genes (pectinases): EXCLUDE (symbol collision - fungal)\n- Papers about Leptospira MPL36 binding to PLG: KEEP (describes mechanism involving human PLG)\n\n**KEPT papers:** 1, 6, 12, 13, 14, 19, 29, 30, 39, 41, 45, 48, 50, 54, 57, 66, 76, 77, 80, 82, 83, 84, 85, 87, 91, 94, 99, 100 (retrieved corpus); plus gene2pubmed: 1, 4, 10, 11, 12, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30\n\n**EXCLUDED:** Papers 2,3,4,5,7,8,9,10,11,15,16,17,18,20,21,22,23,24,25,26,27,28,31,32,33,34,35,36,37,38,40,42,43,44,46,47,49,51,52,53,55,56,58,59,60,61,62,63,64,65,67,68,69,70,71,72,73,74,75,78,79,81,86,88,89,90,92,93,95,96,97,98 (poly-lactide-co-glycolide polymer, Pro-Leu-Gly tripeptide, bacteriocin, or fungal plg); gene2pubmed papers 3,5,6,7,8,9,13,16,26,28 (unrelated proteins or generic genomics).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1970,\n      \"finding\": \"Plasminogen was purified from human plasma by affinity chromatography on L-lysine-substituted Sepharose, demonstrating that plasminogen binds specifically and with high affinity to lysine residues, enabling its isolation with >200-fold purification and a specific activity of 100 caseinolytic units/mg nitrogen.\",\n      \"method\": \"Affinity chromatography (lysine-Sepharose), caseinolytic activity assay, disc-gel electrophoresis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational biochemical purification and activity assay, highly replicated\",\n      \"pmids\": [\"5475635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1967,\n      \"finding\": \"Plasminogen is activated to plasmin by cleavage of a specific peptide bond, yielding a two-chain serine protease (heavy chain containing kringle domains, light chain containing the active site); the mechanism involves limited proteolysis by plasminogen activators.\",\n      \"method\": \"Biochemical peptide chain analysis, N-terminal sequencing, enzyme kinetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization of activation mechanism, foundational and widely replicated\",\n      \"pmids\": [\"4226004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1978,\n      \"finding\": \"Hereditary abnormal plasminogen (reduced enzymatic activity with normal antigen levels) was identified in a patient with recurrent thrombosis and their kindred, demonstrating that PLG mutations cause thrombotic disease through a loss-of-function mechanism affecting catalytic activity.\",\n      \"method\": \"Plasminogen activity assay, antigen quantitation, isoelectric focusing gel electrophoresis, active site titration, family segregation analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods with genetic segregation analysis\",\n      \"pmids\": [\"659588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1976,\n      \"finding\": \"Alpha2-plasmin inhibitor (alpha2-antiplasmin) was isolated from human plasma and shown to instantaneously inhibit plasmin by forming a covalent 1:1 molar complex with the light chain (active site) of plasmin, thereby blocking activator-induced clot lysis; it does not inhibit urokinase at the same rate.\",\n      \"method\": \"Protein purification, SDS-PAGE, immunoelectrophoresis, enzyme inhibition kinetics, cross-linking/complex formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted inhibition with defined stoichiometry and identified interaction domain, widely replicated\",\n      \"pmids\": [\"134998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Platelets bind plasminogen at physiological concentrations via high-affinity lysine-dependent sites (Kd ~2.6 µM on thrombin-stimulated platelets, ~190,000 molecules/cell), and cell surface-bound plasminogen is preferentially activated to plasmin by tissue plasminogen activator, urokinase, or streptokinase, localizing fibrinolytic activity to the platelet surface.\",\n      \"method\": \"Radioiodinated ligand binding assay, Scatchard analysis, omega-aminocarboxylic acid competition, gel analysis of plasmin generation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative binding assay with competitive inhibition and direct plasmin generation measurement\",\n      \"pmids\": [\"3920216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The complete coding sequence of human plasminogen was determined from a full-length liver cDNA clone (2.7 kb insert), revealing the primary structure and correcting several previously reported amino acid residues.\",\n      \"method\": \"cDNA library screening, nucleotide sequencing\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequence determination of full-length PLG cDNA\",\n      \"pmids\": [\"3030813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"A novel carboxypeptidase B (pCPB) was isolated from human plasma by plasminogen-Sepharose affinity chromatography, demonstrating that it is a plasminogen-binding protein; when activated by trypsin it cleaves carboxypeptidase B substrates (hippuryl-Arg, hippuryl-Lys), suggesting a role in removing C-terminal lysines from partially degraded fibrin to regulate plasminogen binding and fibrinolysis.\",\n      \"method\": \"Affinity chromatography, SDS-PAGE, N-terminal sequencing, cDNA cloning, trypsin activation, carboxypeptidase B substrate cleavage assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — protein isolation, cloning, and enzymatic characterization with defined substrates\",\n      \"pmids\": [\"1939207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Angiostatin, a 38 kDa internal fragment of plasminogen containing kringle domains 1–4, was identified as a circulating angiogenesis inhibitor that specifically inhibits endothelial cell proliferation and potently blocks neovascularization and metastatic growth in vivo; intact plasminogen does not share this activity.\",\n      \"method\": \"Protein purification and sequencing from tumor-bearing mouse serum/urine, endothelial cell proliferation assay, in vivo metastasis suppression model, systemic angiostatin administration\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — protein isolated, sequenced, and tested in both in vitro and in vivo functional assays\",\n      \"pmids\": [\"7525077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Individual kringle domains of angiostatin were characterized: kringle 1 (ED50 ~320 nM) and kringle 3 (ED50 ~460 nM) exhibit the most potent anti-proliferative activity against endothelial cells, kringle 2 shows moderate activity, and kringle 4 is ineffective; lysine-binding capability does not correlate with anti-endothelial potency, but proper kringle folding is essential.\",\n      \"method\": \"Recombinant kringle domain expression, endothelial cell proliferation assay, bFGF-stimulated growth inhibition, structure–activity analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic structure-function analysis with recombinant domains and quantitative bioassay\",\n      \"pmids\": [\"8910613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The urokinase-plasmin system controls type IV collagenase (MMP-2 and MMP-9) activity through a cell-surface mechanism: binding of uPA and plasminogen to the cell surface leads to gelatinase activation; inhibition of cell-surface uPA or plasminogen binding blocks gelatinase activation; in soluble phase plasmin degrades both gelatinases, providing a regulatory switch between activation and inactivation.\",\n      \"method\": \"Cell surface binding inhibition, MMP zymography, gelatinase activation assays, soluble phase proteolysis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal assays establishing cell-surface mechanism with epistasis logic\",\n      \"pmids\": [\"9171346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Matrix metalloproteinases MMP-7 (matrilysin) and MMP-9 (gelatinase B) cleave human plasminogen to generate angiostatin-like fragments (~58 kDa, ~42 kDa, ~38 kDa); both enzymes cut N-terminal to kringle domain 5, with MMP-7 and MMP-9 having closely spaced but distinct cleavage sites between kringle 4 and 5, identifying MMPs as angiostatin-converting enzymes.\",\n      \"method\": \"In vitro proteolysis, N-terminal sequencing, SDS-PAGE fragment analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with cleavage site determination by N-terminal sequencing\",\n      \"pmids\": [\"9360944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Streptococcal surface enolase (SEN/alpha-enolase), a 45 kDa glycolytic enzyme displayed on the surface of group A streptococci, binds plasmin(ogen) with high affinity through its C-terminal lysine residue and an additional N-terminal region; SEN-bound plasmin retains proteolytic activity and is protected from inhibition, implicating this interaction in streptococcal tissue invasion.\",\n      \"method\": \"Protein purification and identification, immunoelectron microscopy, dose-dependent activity assay, competitive plasminogen binding inhibition, cross-linking studies with intact streptococci, monoclonal antibody blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods identifying binding mechanism and functional protection of plasmin activity\",\n      \"pmids\": [\"9603964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Angiostatin binds to the alpha/beta subunits of ATP synthase on the surface of human endothelial cells (55 kDa binding partner), distinct from the plasminogen binding site (annexin II, 44 kDa); angiostatin's antiproliferative effect on endothelial cells is inhibited by up to 90% by anti-alpha-subunit ATP synthase antibody, identifying cell-surface ATP synthase as the functional angiostatin receptor.\",\n      \"method\": \"Ligand blot analysis, amino-terminal sequencing, peptide mass fingerprinting, flow cytometry, immunofluorescence, binding studies with recombinant ATP synthase subunit, antibody inhibition of antiproliferative effect\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — protein identified by multiple methods, functional antibody blockade confirmed mechanism\",\n      \"pmids\": [\"10077593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Angiomotin, a novel protein identified by yeast two-hybrid screening with angiostatin kringle domains 1–4, localizes to the leading edge of migrating endothelial cells and mediates angiostatin's inhibitory effects on endothelial cell migration and tube formation; expression of angiomotin increases basal migration but renders cells susceptible to angiostatin inhibition.\",\n      \"method\": \"Yeast two-hybrid screening, fluorescent angiostatin internalization assay, immunofluorescence localization, endothelial migration and tube formation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid with functional validation in cell migration and tube formation assays\",\n      \"pmids\": [\"11257124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Plasmin cleaves the proforms of NGF and BDNF extracellularly; proNGF acts as a high-affinity ligand for p75NTR preferentially inducing apoptosis rather than TrkA-mediated survival, revealing that PLG-dependent extracellular proteolysis switches neurotrophin signaling from survival to cell death.\",\n      \"method\": \"In vitro plasmin cleavage of proneurotrophins, receptor binding assays (p75NTR vs TrkA), neuronal apoptosis assays, TrkA phosphorylation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of proteolytic cleavage combined with receptor-specific functional assays\",\n      \"pmids\": [\"11729324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human plasminogen is a critical host pathogenicity factor for group A streptococcal infection; streptokinase specifically activates human but not mouse plasminogen, and transgenic expression of human plasminogen in mice dramatically increased streptococcal mortality in a streptokinase-dependent manner, establishing the PLG-streptokinase axis as the primary determinant of host species specificity for streptococcal infection.\",\n      \"method\": \"Transgenic mouse model expressing human plasminogen, bacterial infection challenge, genetic deletion of streptokinase, survival analysis with mechanistic comparison\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in transgenic/knockout mouse model with clear mechanistic conclusion\",\n      \"pmids\": [\"15333838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Plg-RKT (C9orf46 homolog) was identified as a novel integral membrane plasminogen receptor that exposes a C-terminal lysine on the cell surface; it is induced during monocyte differentiation, co-localizes with uPAR on the cell surface, interacts directly with tissue plasminogen activator, and markedly promotes cell surface plasminogen activation.\",\n      \"method\": \"MudPIT proteomics with carboxypeptidase B treatment, flow cytometry, co-localization studies, plasminogen activation assay, database mining for expression\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — discovery by quantitative proteomics plus functional plasminogen activation assay and co-localization\",\n      \"pmids\": [\"19897580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Extracellular hsp90alpha, secreted via exosomes by invasive cancer cells, interacts with tissue plasminogen activator (tPA) and, together with annexin II (also present in exosomes), activates plasmin; this extracellular hsp90alpha-tPA complex promotes plasmin-dependent cancer cell motility.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, plasmin activation assay, migration assay with inhibitors, exosome isolation and characterization\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and functional assay in single study; plasmin activation confirmed by direct assay\",\n      \"pmids\": [\"20553606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plg-RKT plays a key role in macrophage invasion, chemotactic migration, and in vivo recruitment: anti-Plg-RKT antibody inhibited uPA-mediated plasminogen activation (by 39%), Matrigel invasion in response to MCP-1 (by 54%), chemotactic migration (by 64%), and peritoneal macrophage recruitment in thioglycollate-induced peritonitis (by 58%); anti-Plg-RKT antibody had no additional effect in plasminogen-null mice, establishing plasminogen-dependence.\",\n      \"method\": \"Anti-Plg-RKT mAb blockade, Matrigel invasion assay, chemotaxis assay, mouse peritonitis model, plasminogen-null mice comparison, pro-MMP-9 activation measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with genetic (plasminogen-null) epistasis confirmation\",\n      \"pmids\": [\"21940822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plg-RKT is expressed on the surface of catecholaminergic cells (chromaffin cells, PC12 cells); it co-immunoprecipitates with uPAR, is an integral plasma membrane protein, and its overexpression markedly enhances plasminogen activation; cells overexpressing Plg-RKT show 51% reduction in nicotine-evoked norepinephrine release, while antibody blockade of endogenous Plg-RKT increases norepinephrine release, establishing Plg-RKT as a regulator of catecholamine secretion through plasmin-mediated proteolysis of prohormones.\",\n      \"method\": \"Stable overexpression, antibody blockade, co-immunoprecipitation with uPAR, FACS analysis, phase partitioning, plasminogen activation assay, [3H]norepinephrine secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional evidence (overexpression + antibody blockade) with co-IP and direct secretion assay\",\n      \"pmids\": [\"21795689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of Plg-RKT in mice demonstrated that Plg-RKT is required for plasminogen binding to macrophages and for macrophage migration in vivo in experimental peritonitis; Plg-RKT deficiency also causes complete failure of lactation (all offspring of Plg-RKT−/− females die within 2 days of birth) and affects female but not male growth rates.\",\n      \"method\": \"Homologous recombination knockout mice, macrophage plasminogen binding assay, peritonitis recruitment model, lactation phenotype assessment\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with quantitative plasminogen binding and in vivo functional phenotype\",\n      \"pmids\": [\"27714956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A heterozygous missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of PLG was identified in patients with hereditary angioedema with normal C1-INH, establishing a novel gain-of-function PLG mutation as a cause of hereditary angioedema through autosomal dominant inheritance.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, family segregation analysis, clinical phenotyping\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification in multiple independent families with clear autosomal dominant segregation\",\n      \"pmids\": [\"28795768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plg-RKT is essential for mammary lobuloalveolar development and lactation: Plg-RKT−/− mice show blocked lobuloalveolar development due to hypertrophic fibrotic stroma, massive fibrin accumulation in alveoli/ducts, macrophage infiltration, 12-fold downregulation of EGF, absent epithelial cell proliferation, downregulation of pro-survival protein Mcl-1, and increased apoptosis; fibrinogen heterozygosity reduced fibrin accumulation but did not rescue lobuloalveolar defects, indicating plasminogen-independent mechanisms also contribute.\",\n      \"method\": \"Knockout mouse mammary gland analysis, immunohistochemistry for fibrin/macrophages/proliferation/apoptosis, transcriptional profiling, fibrinogen genetic reduction (compound knockout)\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with compound knockouts, multiple molecular readouts establishing mechanism\",\n      \"pmids\": [\"29495105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Plasminogen and plasmin promote macrophage M2-like polarization and efferocytosis through transient STAT3 phosphorylation: in vitro, Plg/plasmin increased CD206/Arginase-1 and IL-10/TGF-β while suppressing LPS/IFN-induced M1 markers; in vivo, Plg−/− and Plg-RKT−/− mice showed increased M1-like macrophages, decreased CCL2, defective IL-4-induced M2 polarization, and reduced phagocytosis of apoptotic neutrophils.\",\n      \"method\": \"Murine pleurisy model, bone marrow-derived macrophage polarization assays, STAT3 phosphorylation western blot, flow cytometry (M1/M2 markers), efferocytosis assay in vivo and in vitro\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout models combined with in vitro mechanistic signaling assays in multiple cell types\",\n      \"pmids\": [\"31316511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Plg-RKT is differentially expressed on proinflammatory monocyte/macrophage subsets (CD14++CD16+ human monocytes and Ly6Chigh mouse monocytes show highest expression); directional migration of proinflammatory monocytes is plasmin-dependent and abolished by anti-Plg-RKT mAb, ε-aminocaproic acid, aprotinin, and the aminoterminal fragment of uPA; Plg-RKT−/− mice show significantly less Ly6Chigh monocyte recruitment in peritonitis.\",\n      \"method\": \"Flow cytometry for Plg-RKT expression on monocyte subsets, plasminogen binding assay, directional migration assay with multiple inhibitors, in vivo peritonitis model in Plg-RKT−/− mice, immunohistochemistry in human carotid plaques\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple inhibitor strategies + genetic knockout with in vivo and in vitro concordant results\",\n      \"pmids\": [\"31221672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plg-RKT regulates cutaneous wound healing through plasminogen-dependent fibrinolysis and myeloid cell-mediated inflammation: Plg-RKT−/− mice show delayed wound closure during the proliferation phase, dysregulated cytokine expression, and impaired fibrin clearance; genetic reduction of fibrinogen levels by 50% completely abrogated the wound healing delay, and Plg-RKT deletion specifically in keratinocytes paradoxically accelerated healing with upregulation of filaggrin and caspase 14.\",\n      \"method\": \"Standardized burn wound model, conditional/constitutive Plg-RKT knockout mice (myeloid- and keratinocyte-specific), fibrin clearance measurement, fibrinogen compound knockouts, transcriptional profiling, cytokine quantitation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional knockouts with genetic epistasis (fibrinogen reduction) establishing mechanistic pathway\",\n      \"pmids\": [\"33311441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT on activated human and murine platelets retains platelet-derived plasminogen (secreted from alpha-granules) on the platelet membrane via a lysine-dependent mechanism; Plg-RKT co-localizes with platelet-derived plasminogen on activated platelet membranes; Plg-RKT−/− platelets show significantly attenuated plasminogen membrane exposure after activation; platelet-membrane-retained plasminogen drives local fibrinolysis by enhancing cell surface plasminogen activation.\",\n      \"method\": \"Western blotting of platelet membrane fractions, confocal microscopy, flow cytometry, ε-aminocaproic acid competition, fluorescent plasminogen-deficient clot lysis assay, turbidimetric clot lysis assay, Plg-RKT−/− mouse platelets\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including genetic knockout validation and direct fibrinolysis assay\",\n      \"pmids\": [\"32842150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLG silencing in HBV-positive hepatocellular carcinoma cells promoted apoptosis in vitro and suppressed tumor xenograft growth in vivo by inhibiting HBV replication; mechanistically, PLG activates SRC (a downstream target), which promotes Hippo pathway signaling to support HBV-HCC cell survival.\",\n      \"method\": \"siRNA knockdown, flow cytometry for apoptosis (TUNEL), subcutaneous xenograft model, qRT-PCR, western blot, KEGG/GO pathway analysis\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 — bioinformatics-driven, single-lab study with limited mechanistic validation of PLG-SRC-Hippo axis\",\n      \"pmids\": [\"33594307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT regulates adipose function and metabolic homeostasis: Plg-RKT is highly expressed in human and mouse adipose tissue and markedly upregulated during adipogenesis; Plg-RKT−/− mice on high-fat diet develop increased adipose and hepatic inflammation, macrophage/T-cell accumulation, fibrosis, hepatic steatosis, and insulin resistance; Plg-RKT regulates PPARγ and other adipogenic molecule expression, suggesting a novel role in the adipogenic transcriptional program.\",\n      \"method\": \"Immunofluorescence of human/mouse adipose tissue, high-fat diet mouse model, Plg-RKT−/− mice, 3T3-L1 and primary preadipocyte differentiation assays, insulin signaling western blot, RT-PCR for PPARγ\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple metabolic readouts, but adipogenic mechanism requires further validation\",\n      \"pmids\": [\"34897983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Plg-RKT is highly expressed by scar-associated macrophages (SAMs) in fibrotic liver; PLG treatment transforms bone-marrow-derived macrophages into SAMs expressing pro-fibrotic genes, an effect blocked by Plg-RKT knockdown; selective in vivo knockdown of Plg-RKT in intrahepatic macrophages using siRNA-GeRPs reduced SAM numbers and alleviated BDL- and CCl4-induced liver fibrosis.\",\n      \"method\": \"Single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), siRNA-GeRPs macrophage-selective knockdown, bone marrow-derived macrophage treatment assays, BDL and CCl4 mouse liver fibrosis models\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — selective in vivo knockdown with in vitro mechanistic rescue, multiple fibrosis models\",\n      \"pmids\": [\"37207518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liver-secreted plasminogen signals directly to muscle satellite cells (via Plg-RKT/ERK kinase) to promote their proliferation during caloric restriction (CR); knockdown of circulating plasminogen prevents CR-induced satellite cell expansion; loss of Plg-RKT is also sufficient to prevent CR-related satellite cell expansion; these findings were replicated in human CALERIE trial participants.\",\n      \"method\": \"MetRSL274G transgenic mouse proteomics to identify liver-secreted factors, plasminogen knockdown (circulating), Plg-RKT knockout mice, satellite cell isolation and counting, ERK phosphorylation assay, human CALERIE trial analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models (knockdown + knockout) with defined Plg-RKT/ERK signaling axis and human replication\",\n      \"pmids\": [\"38442019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In renal cell carcinoma, FABP1+ tumor cells signal to endothelial cells via the PLG-PLAT (tissue plasminogen activator) axis to promote plasmin-related tumor angiogenesis; spatial transcriptomics showed co-localization of FABP1+ tumors with PLAT+ endothelial cells, and receptor-ligand interaction analysis confirmed PLG-PLAT as a functional signaling axis between tumor and endothelial compartments.\",\n      \"method\": \"Single-cell RNA sequencing, spatial transcriptomics, receptor-ligand interaction analysis, preclinical tumor models, FABP1-PLG-PLAT axis functional experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — computational interaction inference with limited direct mechanistic validation of the PLG-PLAT axis\",\n      \"pmids\": [\"40518526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Three novel PLG gene mutations (C166Y, Y264S, IVS10-7T/G) were identified in patients with severe hypoplasminogenemia, a multisystemic disorder causing deficient extravascular fibrinolysis manifesting as ligneous conjunctivitis, periodontitis, hydrocephalus, and other mucosal membrane abnormalities; molecular genetic analysis of 23 cases confirmed that homozygous or compound-heterozygous PLG mutations underlie the clinical phenotype.\",\n      \"method\": \"Sanger sequencing, molecular genetic analysis, clinical phenotyping\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification of novel loss-of-function mutations with clear phenotypic consequence, though mechanism is by inference from known PLG biology\",\n      \"pmids\": [\"21174000\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Plasminogen (PLG) is the zymogen of the broad-spectrum serine protease plasmin, activated by limited proteolysis (cleavage between kringle and serine-protease domains) by tissue-type or urokinase-type plasminogen activators; plasminogen binds to cell surfaces via high-affinity interactions with C-terminal lysine residues on proteins including the transmembrane receptor Plg-RKT, annexin II, and alpha-enolase, where activation to plasmin is markedly enhanced and the resulting proteolytic activity is focused on fibrinolysis, extracellular matrix remodeling (through MMP activation), prohormone processing (generating catecholamine-regulatory peptides), proneurotrophin cleavage (switching p75NTR/TrkA signaling balance), and macrophage/monocyte recruitment and polarization; internal PLG kringle fragments (angiostatin, kringles 1–4) act as potent endothelial cell antiproliferative agents by binding ATP synthase and angiomotin on the endothelial surface; loss-of-function PLG mutations cause hypoplasminogenemia with defective mucosal wound healing, while gain-of-function kringle mutations cause hereditary angioedema; the dedicated transmembrane receptor Plg-RKT co-localizes with uPAR to orchestrate cell-surface plasminogen activation and is required for macrophage migration, mammary lobuloalveolar development and lactation, wound healing, resolution of inflammation, satellite cell expansion during caloric restriction, and metabolic homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLG encodes plasminogen, the zymogen of the serine protease plasmin, whose activation at the cell surface is critically regulated by the integral membrane receptor Plg-RKT; Plg-RKT exposes a C-terminal lysine that tethers plasminogen and physically associates with uPAR and tissue plasminogen activator to concentrate and accelerate plasminogen-to-plasmin conversion [PMID:19897580, PMID:32662180]. Cell-surface plasminogen activation through Plg-RKT drives macrophage and monocyte chemotactic migration, peritoneal recruitment, efferocytosis of apoptotic cells, and M2 macrophage polarization via STAT3 phosphorylation, while also enabling plasmin-dependent pro-MMP-9 activation and fibrin clearance during wound healing [PMID:21940822, PMID:31316511, PMID:33311441]. Beyond innate immunity and fibrinolysis, the plasminogen–Plg-RKT axis is required for mammary lobuloalveolar development and lactation through both fibrinolytic and fibrinolysis-independent mechanisms, regulates adipose tissue homeostasis and insulin sensitivity, promotes hepatic scar-associated macrophage differentiation in liver fibrosis, and mediates caloric-restriction-induced muscle satellite cell expansion via ERK signaling [PMID:29495105, PMID:34897983, PMID:37207518, PMID:38442019]. On activated platelets, Plg-RKT retains platelet-derived plasminogen on the membrane surface to drive local fibrinolysis [PMID:32842150].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"The chromosomal location of PLG was anchored by demonstrating tight genetic linkage between the Lp(a) lipoprotein locus and PLG on chromosome 6q, providing the genomic framework for studying plasminogen function.\",\n      \"evidence\": \"Family linkage analysis with lod score 12.73\",\n      \"pmids\": [\"2966760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Linkage only; no functional mechanism connecting Lp(a) regulation to PLG activity was established\", \"No biochemical characterization of PLG protein in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The discovery of Plg-RKT as a novel integral membrane plasminogen receptor with an exposed C-terminal lysine resolved the long-standing question of how plasminogen is concentrated and activated at cell surfaces, showing that Plg-RKT co-localizes with uPAR and interacts with tPA to markedly enhance plasminogen activation.\",\n      \"evidence\": \"MudPIT proteomics, carboxypeptidase B treatment, co-immunoprecipitation, cell-surface plasminogen activation assays in eukaryotic cells\",\n      \"pmids\": [\"19897580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for Plg-RKT in plasminogen-dependent processes not yet tested\", \"Stoichiometry and structural basis of the Plg-RKT–uPAR complex unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Functional studies established that Plg-RKT-mediated plasminogen activation is required for macrophage invasion, chemotaxis, and peritoneal recruitment, with genetic epistasis in plasminogen-null mice proving plasminogen-dependence; concurrently, Plg-RKT was shown to regulate catecholamine secretion, broadening the physiological reach of cell-surface plasminogen activation.\",\n      \"evidence\": \"Anti-Plg-RKT mAb blockade, Matrigel invasion, chemotaxis assay, mouse peritonitis model with Plg−/− epistasis; GFP-fusion, co-IP with uPAR, [3H]norepinephrine secretion assay in catecholaminergic cells\",\n      \"pmids\": [\"21940822\", \"21795689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking plasmin generation to MMP-9 activation at the molecular level not fully resolved\", \"Catecholamine regulation relied on a single cell model without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generation of Plg-RKT knockout mice provided definitive in vivo evidence that Plg-RKT is required for plasminogen binding to macrophages and macrophage recruitment, and unexpectedly revealed an essential role in lactation, with all pups of Plg-RKT−/− dams dying within 2 days.\",\n      \"evidence\": \"Homologous recombination KO mice, peritonitis model, plasminogen binding assay, reproduction phenotyping\",\n      \"pmids\": [\"27714956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of lactation failure not yet characterized\", \"Whether the lactation defect is plasminogen-dependent or independent was unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The lactation defect was mechanistically dissected: Plg-RKT is required for mammary lobuloalveolar development through EGF signaling, epithelial proliferation, and prevention of apoptosis; genetic reduction of fibrinogen did not rescue lobuloalveolar defects, establishing that Plg-RKT functions through both fibrinolytic and fibrinolysis-independent pathways.\",\n      \"evidence\": \"Plg-RKT−/− mice, digenic cross with fibrinogen heterozygosity, histology, immunofluorescence, Ki67/TUNEL assays, transcriptional profiling\",\n      \"pmids\": [\"29495105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of fibrinolysis-independent signaling pathway not determined\", \"Whether plasminogen itself or only plasmin is required for mammary development unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Plasminogen and plasmin were shown to drive macrophage M2 polarization and efferocytosis through STAT3 phosphorylation, identifying a specific intracellular signaling axis downstream of the plasminogen–Plg-RKT interaction; simultaneously, Plg-RKT was found to be preferentially expressed on proinflammatory monocyte subsets, directing their plasmin-dependent migration.\",\n      \"evidence\": \"Plg−/− and Plg-RKT−/− BMDMs, STAT3 phosphorylation, flow cytometry, murine pleurisy/peritonitis, efferocytosis assay; human CD14++CD16+ monocyte phenotyping, anti-Plg-RKT mAb, Transwell migration\",\n      \"pmids\": [\"31316511\", \"31221672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptor or adaptor linking Plg-RKT to STAT3 activation not identified\", \"Whether STAT3 mediates all downstream immune functions of plasminogen unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific conditional knockouts revealed opposing roles of Plg-RKT in wound healing—myeloid Plg-RKT promotes healing by enabling fibrin clearance and cytokine regulation, while keratinocyte Plg-RKT restrains healing—with fibrinogen genetic reduction rescuing the myeloid knockout delay, firmly establishing fibrin accumulation as the key downstream effector in this context.\",\n      \"evidence\": \"Myeloid- and keratinocyte-specific conditional KO mice, standardized burn wound model, fibrinogen heterozygous cross, cytokine profiling, qPCR\",\n      \"pmids\": [\"33311441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How keratinocyte Plg-RKT restrains wound healing at the molecular level remains unexplained\", \"Wound healing studies limited to burn model; generalizability to other wound types not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Plg-RKT was demonstrated on activated platelets where it retains platelet-derived plasminogen on the membrane to drive local fibrinolysis, extending the receptor's role beyond leukocytes to hemostasis; separately, Plg-RKT−/− mice on high-fat diet showed exacerbated obesity, hepatic steatosis, and insulin resistance, linking plasminogen activation to metabolic homeostasis through PPARγ regulation and adipogenesis.\",\n      \"evidence\": \"Platelet membrane fractionation, confocal microscopy, flow cytometry, Plg-RKT−/− mice, fluorescent fibrinolysis assay; HFD model, glucose/insulin tolerance tests, 3T3-L1/primary preadipocyte differentiation, Western blot\",\n      \"pmids\": [\"32842150\", \"34897983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether platelet Plg-RKT contributes to thrombolysis in thrombotic disease models not tested\", \"Metabolic phenotype from single lab; PPARγ regulation mechanism not elucidated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Single-cell approaches revealed Plg-RKT as a marker of scar-associated macrophages in fibrotic liver, and selective in vivo macrophage Plg-RKT knockdown reduced SAM accumulation and alleviated fibrosis, demonstrating a pro-fibrotic role for the plasminogen–Plg-RKT axis in chronic liver disease.\",\n      \"evidence\": \"scRNA-seq, CyTOF, siRNA-GeRP macrophage-selective in vivo knockdown, BMM culture with PLG, BDL and CCl4 liver fibrosis models\",\n      \"pmids\": [\"37207518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether therapeutic targeting of Plg-RKT can reverse (not just prevent) established fibrosis is untested\", \"Signaling pathway downstream of Plg-RKT in SAM transformation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Liver-secreted plasminogen was identified as the endocrine signal mediating muscle satellite cell expansion during caloric restriction, acting through Plg-RKT and ERK kinase signaling, with validation in human CALERIE participants establishing translational relevance.\",\n      \"evidence\": \"MetRSL274G transgenic mice for liver-secretome identification, plasminogen knockdown, Plg-RKT−/− mice, ERK signaling assay, satellite cell quantification, human CALERIE cohort\",\n      \"pmids\": [\"38442019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERK activation is direct or requires intermediary kinases downstream of Plg-RKT unknown\", \"Mechanism by which caloric restriction upregulates hepatic plasminogen secretion not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct signaling mechanism linking Plg-RKT engagement by plasminogen to intracellular kinase cascades (STAT3, ERK) remains undefined—no adaptor, co-receptor kinase, or structural basis for signal transduction across the membrane has been identified, leaving the central question of how a small transmembrane receptor lacking a canonical signaling domain activates diverse downstream pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the Plg-RKT–uPAR–plasminogen ternary complex exists\", \"Adaptor or co-receptor kinase linking Plg-RKT to STAT3 and ERK unidentified\", \"Relative contribution of plasminogen binding versus plasmin catalytic activity to signaling outcomes not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 8, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLAUR\", \"PLAT\", \"PLGRKT\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway section — I accidentally included a GO term. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"PLG encodes plasminogen, the zymogen of the serine protease plasmin, whose activation at the cell surface is critically regulated by the integral membrane receptor Plg-RKT; Plg-RKT exposes a C-terminal lysine that tethers plasminogen and physically associates with uPAR and tissue plasminogen activator to concentrate and accelerate plasminogen-to-plasmin conversion [PMID:19897580, PMID:32662180]. Cell-surface plasminogen activation through Plg-RKT drives macrophage and monocyte chemotactic migration, peritoneal recruitment, efferocytosis of apoptotic cells, and M2 macrophage polarization via STAT3 phosphorylation, while also enabling plasmin-dependent pro-MMP-9 activation and fibrin clearance during wound healing [PMID:21940822, PMID:31316511, PMID:33311441]. Beyond innate immunity and fibrinolysis, the plasminogen–Plg-RKT axis is required for mammary lobuloalveolar development and lactation through both fibrinolytic and fibrinolysis-independent mechanisms, regulates adipose tissue homeostasis and insulin sensitivity, promotes hepatic scar-associated macrophage differentiation in liver fibrosis, and mediates caloric-restriction-induced muscle satellite cell expansion via ERK signaling [PMID:29495105, PMID:34897983, PMID:37207518, PMID:38442019]. On activated platelets, Plg-RKT retains platelet-derived plasminogen on the membrane surface to drive local fibrinolysis [PMID:32842150].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"The chromosomal location of PLG was anchored by demonstrating tight genetic linkage between the Lp(a) lipoprotein locus and PLG on chromosome 6q, providing the genomic framework for studying plasminogen function.\",\n      \"evidence\": \"Family linkage analysis with lod score 12.73\",\n      \"pmids\": [\"2966760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Linkage only; no functional mechanism connecting Lp(a) regulation to PLG activity was established\", \"No biochemical characterization of PLG protein in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The discovery of Plg-RKT as a novel integral membrane plasminogen receptor with an exposed C-terminal lysine resolved the long-standing question of how plasminogen is concentrated and activated at cell surfaces, showing that Plg-RKT co-localizes with uPAR and interacts with tPA to markedly enhance plasminogen activation.\",\n      \"evidence\": \"MudPIT proteomics, carboxypeptidase B treatment, co-immunoprecipitation, cell-surface plasminogen activation assays in eukaryotic cells\",\n      \"pmids\": [\"19897580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for Plg-RKT in plasminogen-dependent processes not yet tested\", \"Stoichiometry and structural basis of the Plg-RKT–uPAR complex unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Functional studies established that Plg-RKT-mediated plasminogen activation is required for macrophage invasion, chemotaxis, and peritoneal recruitment, with genetic epistasis in plasminogen-null mice proving plasminogen-dependence; concurrently, Plg-RKT was shown to regulate catecholamine secretion, broadening the physiological reach of cell-surface plasminogen activation.\",\n      \"evidence\": \"Anti-Plg-RKT mAb blockade, Matrigel invasion, chemotaxis assay, mouse peritonitis model with Plg−/− epistasis; GFP-fusion, co-IP with uPAR, [3H]norepinephrine secretion assay in catecholaminergic cells\",\n      \"pmids\": [\"21940822\", \"21795689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking plasmin generation to MMP-9 activation at the molecular level not fully resolved\", \"Catecholamine regulation relied on a single cell model without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generation of Plg-RKT knockout mice provided definitive in vivo evidence that Plg-RKT is required for plasminogen binding to macrophages and macrophage recruitment, and unexpectedly revealed an essential role in lactation, with all pups of Plg-RKT−/− dams dying within 2 days.\",\n      \"evidence\": \"Homologous recombination KO mice, peritonitis model, plasminogen binding assay, reproduction phenotyping\",\n      \"pmids\": [\"27714956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of lactation failure not yet characterized\", \"Whether the lactation defect is plasminogen-dependent or independent was unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The lactation defect was mechanistically dissected: Plg-RKT is required for mammary lobuloalveolar development through EGF signaling, epithelial proliferation, and prevention of apoptosis; genetic reduction of fibrinogen did not rescue lobuloalveolar defects, establishing that Plg-RKT functions through both fibrinolytic and fibrinolysis-independent pathways.\",\n      \"evidence\": \"Plg-RKT−/− mice, digenic cross with fibrinogen heterozygosity, histology, immunofluorescence, Ki67/TUNEL assays, transcriptional profiling\",\n      \"pmids\": [\"29495105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of fibrinolysis-independent signaling pathway not determined\", \"Whether plasminogen itself or only plasmin is required for mammary development unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Plasminogen and plasmin were shown to drive macrophage M2 polarization and efferocytosis through STAT3 phosphorylation, identifying a specific intracellular signaling axis downstream of the plasminogen–Plg-RKT interaction; simultaneously, Plg-RKT was found to be preferentially expressed on proinflammatory monocyte subsets, directing their plasmin-dependent migration.\",\n      \"evidence\": \"Plg−/− and Plg-RKT−/− BMDMs, STAT3 phosphorylation, flow cytometry, murine pleurisy/peritonitis, efferocytosis assay; human CD14++CD16+ monocyte phenotyping, anti-Plg-RKT mAb, Transwell migration\",\n      \"pmids\": [\"31316511\", \"31221672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptor or adaptor linking Plg-RKT to STAT3 activation not identified\", \"Whether STAT3 mediates all downstream immune functions of plasminogen unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific conditional knockouts revealed opposing roles of Plg-RKT in wound healing—myeloid Plg-RKT promotes healing by enabling fibrin clearance and cytokine regulation, while keratinocyte Plg-RKT restrains healing—with fibrinogen genetic reduction rescuing the myeloid knockout delay, firmly establishing fibrin accumulation as the key downstream effector in this context.\",\n      \"evidence\": \"Myeloid- and keratinocyte-specific conditional KO mice, standardized burn wound model, fibrinogen heterozygous cross, cytokine profiling, qPCR\",\n      \"pmids\": [\"33311441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How keratinocyte Plg-RKT restrains wound healing at the molecular level remains unexplained\", \"Wound healing studies limited to burn model; generalizability to other wound types not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Plg-RKT was demonstrated on activated platelets where it retains platelet-derived plasminogen on the membrane to drive local fibrinolysis, extending the receptor's role beyond leukocytes to hemostasis; separately, Plg-RKT−/− mice on high-fat diet showed exacerbated obesity, hepatic steatosis, and insulin resistance, linking plasminogen activation to metabolic homeostasis through PPARγ regulation and adipogenesis.\",\n      \"evidence\": \"Platelet membrane fractionation, confocal microscopy, flow cytometry, Plg-RKT−/− mice, fluorescent fibrinolysis assay; HFD model, glucose/insulin tolerance tests, 3T3-L1/primary preadipocyte differentiation, Western blot\",\n      \"pmids\": [\"32842150\", \"34897983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether platelet Plg-RKT contributes to thrombolysis in thrombotic disease models not tested\", \"Metabolic phenotype from single lab; PPARγ regulation mechanism not elucidated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Single-cell approaches revealed Plg-RKT as a marker of scar-associated macrophages in fibrotic liver, and selective in vivo macrophage Plg-RKT knockdown reduced SAM accumulation and alleviated fibrosis, demonstrating a pro-fibrotic role for the plasminogen–Plg-RKT axis in chronic liver disease.\",\n      \"evidence\": \"scRNA-seq, CyTOF, siRNA-GeRP macrophage-selective in vivo knockdown, BMM culture with PLG, BDL and CCl4 liver fibrosis models\",\n      \"pmids\": [\"37207518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether therapeutic targeting of Plg-RKT can reverse established fibrosis is untested\", \"Signaling pathway downstream of Plg-RKT in SAM transformation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Liver-secreted plasminogen was identified as the endocrine signal mediating muscle satellite cell expansion during caloric restriction, acting through Plg-RKT and ERK kinase signaling, with validation in human CALERIE participants establishing translational relevance.\",\n      \"evidence\": \"MetRSL274G transgenic mice for liver-secretome identification, plasminogen knockdown, Plg-RKT−/− mice, ERK signaling assay, satellite cell quantification, human CALERIE cohort\",\n      \"pmids\": [\"38442019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERK activation is direct or requires intermediary kinases downstream of Plg-RKT unknown\", \"Mechanism by which caloric restriction upregulates hepatic plasminogen secretion not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct signaling mechanism linking Plg-RKT engagement by plasminogen to intracellular kinase cascades (STAT3, ERK) remains undefined—no adaptor, co-receptor kinase, or structural basis for signal transduction across the membrane has been identified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the Plg-RKT–uPAR–plasminogen ternary complex exists\", \"Adaptor or co-receptor kinase linking Plg-RKT to STAT3 and ERK unidentified\", \"Relative contribution of plasminogen binding versus plasmin catalytic activity to signaling outcomes not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 8, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLAUR\", \"PLAT\", \"PLGRKT\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Plasminogen (PLG) is the circulating zymogen of plasmin, a broad-spectrum serine protease central to fibrinolysis, extracellular matrix remodeling, macrophage recruitment and polarization, proneurotrophin processing, prohormone cleavage, and angiogenesis regulation. Plasminogen is activated by tissue-type and urokinase-type plasminogen activators via limited proteolysis at the kringle–serine protease domain junction, a process markedly enhanced when plasminogen is bound to cell-surface receptors—principally Plg-RKT, annexin II, and alpha-enolase—through lysine-dependent interactions [PMID:5475635, PMID:19897580, PMID:9603964]; cell-surface plasmin in turn activates MMP-2/MMP-9 to drive matrix degradation, cleaves proneurotrophins to switch p75NTR/TrkA signaling balance, and promotes M2-like macrophage polarization via STAT3 phosphorylation [PMID:9171346, PMID:11729324, PMID:31316511]. Internal kringle 1–4 fragments (angiostatin), generated by MMP-mediated cleavage, inhibit endothelial cell proliferation and neovascularization by binding cell-surface ATP synthase and angiomotin [PMID:7525077, PMID:10077593, PMID:11257124]. Homozygous or compound-heterozygous loss-of-function PLG mutations cause hypoplasminogenemia with ligneous conjunctivitis and mucosal fibrin deposition, while a heterozygous gain-of-function kringle 3 mutation (K330E) causes hereditary angioedema [PMID:21174000, PMID:28795768].\",\n  \"teleology\": [\n    {\n      \"year\": 1967,\n      \"claim\": \"Resolving how an inactive zymogen becomes an active protease, biochemical analysis showed plasminogen is converted to the two-chain serine protease plasmin by limited proteolysis at a specific peptide bond, establishing the fundamental activation mechanism.\",\n      \"evidence\": \"Peptide chain analysis, N-terminal sequencing, and enzyme kinetics on purified plasminogen/plasmin\",\n      \"pmids\": [\"4226004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activator identity and specificity not yet defined\", \"Structural basis of kringle domain–active site chain association unknown\"]\n    },\n    {\n      \"year\": 1970,\n      \"claim\": \"Demonstrating the molecular basis of plasminogen's surface-binding capacity, affinity chromatography on lysine-Sepharose showed that plasminogen binds specifically to lysine residues, enabling its efficient purification and predicting lysine-dependent receptor interactions.\",\n      \"evidence\": \"Lysine-Sepharose affinity chromatography with caseinolytic activity assay\",\n      \"pmids\": [\"5475635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of physiological cell-surface lysine-bearing receptors unknown\", \"Contribution of individual kringle domains to lysine binding not resolved\"]\n    },\n    {\n      \"year\": 1976,\n      \"claim\": \"Identifying the principal physiological brake on plasmin, alpha2-antiplasmin was shown to form an instantaneous 1:1 stoichiometric complex with the plasmin active site, establishing the primary mechanism of plasmin inactivation in plasma.\",\n      \"evidence\": \"Protein purification, SDS-PAGE, and enzyme inhibition kinetics demonstrating covalent complex with plasmin light chain\",\n      \"pmids\": [\"134998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rate constants for inhibition of cell-surface-bound versus free plasmin not compared\", \"Mechanism of fibrin-mediated protection from inhibition not defined\"]\n    },\n    {\n      \"year\": 1978,\n      \"claim\": \"Linking PLG to human disease, identification of hereditary dysfunctional plasminogen (normal antigen, reduced activity) in a family with recurrent thrombosis demonstrated that PLG loss-of-function mutations cause thrombophilia.\",\n      \"evidence\": \"Plasminogen activity assay, antigen quantitation, active site titration, and family segregation\",\n      \"pmids\": [\"659588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the mutation not determined\", \"Prevalence and spectrum of PLG mutations in thrombophilia unclear\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Establishing that cell surfaces are privileged sites for plasmin generation, platelets were shown to bind plasminogen at high capacity via lysine-dependent sites and to preferentially support its activation by tPA, urokinase, and streptokinase.\",\n      \"evidence\": \"Radioiodinated ligand binding, Scatchard analysis, and cell-surface plasmin generation assay on thrombin-stimulated platelets\",\n      \"pmids\": [\"3920216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of platelet plasminogen receptors not determined\", \"Relative contribution of platelet- versus fibrin-surface plasmin to clot lysis unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Revealing a cryptic anti-angiogenic function within the plasminogen molecule, angiostatin (kringles 1–4) was identified as a circulating inhibitor of endothelial proliferation and metastatic neovascularization, distinct from any activity of intact plasminogen.\",\n      \"evidence\": \"Purification from tumor-bearing mouse serum, N-terminal sequencing, endothelial proliferation assay, and in vivo metastasis suppression\",\n      \"pmids\": [\"7525077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological protease(s) generating angiostatin in vivo not identified\", \"Receptor mediating anti-proliferative activity unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connecting plasminogen to matrix metalloproteinase cascades and angiostatin generation, cell-surface uPA/plasminogen activation was shown to activate MMP-2 and MMP-9, while MMP-7 and MMP-9 were identified as angiostatin-converting enzymes that cleave plasminogen between kringles 4 and 5.\",\n      \"evidence\": \"Cell-surface binding inhibition, MMP zymography, in vitro proteolysis with N-terminal sequencing of cleavage products\",\n      \"pmids\": [\"9171346\", \"9360944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of MMP-generated angiostatin versus other proteolytic pathways not established\", \"Regulation of the MMP–plasminogen crosstalk in specific tissues unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying the functional angiostatin receptor, cell-surface ATP synthase alpha/beta subunits on endothelial cells were shown to bind angiostatin, and antibody blockade of the alpha subunit abolished up to 90% of angiostatin's anti-proliferative effect.\",\n      \"evidence\": \"Ligand blot, N-terminal sequencing, peptide mass fingerprinting, flow cytometry, and antibody inhibition of proliferation\",\n      \"pmids\": [\"10077593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from surface ATP synthase engagement not characterized\", \"Relative contribution of ATP synthase versus angiomotin to angiostatin effects in vivo unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Expanding plasminogen's biological reach beyond fibrinolysis, plasmin was shown to cleave proNGF and proBDNF extracellularly, converting them from p75NTR-selective pro-apoptotic ligands into TrkA-activating mature neurotrophins, and angiomotin was identified as a second angiostatin-binding mediator of endothelial migration inhibition.\",\n      \"evidence\": \"In vitro plasmin cleavage of proneurotrophins with receptor binding and apoptosis assays; yeast two-hybrid identification of angiomotin with migration and tube-formation assays\",\n      \"pmids\": [\"11729324\", \"11257124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement of plasmin for proneurotrophin processing not established by genetic models at this time\", \"Relative contributions of angiomotin and ATP synthase to angiostatin signaling unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating plasminogen as a host susceptibility factor in infection, streptokinase-specific activation of human (but not mouse) plasminogen was shown to be the key determinant of group A streptococcal virulence, as transgenic expression of human PLG in mice dramatically increased mortality in a streptokinase-dependent manner.\",\n      \"evidence\": \"Transgenic human-PLG mouse infection model with streptokinase-deletion bacteria and survival analysis\",\n      \"pmids\": [\"15333838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pathogen-hijacked plasmin acts through fibrinolysis, matrix degradation, or immune evasion not dissected\", \"Relevance to other plasminogen-activating pathogens not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying the dedicated cell-surface receptor that orchestrates plasminogen activation, Plg-RKT was discovered as an integral membrane protein exposing a C-terminal lysine, co-localizing with uPAR, and markedly enhancing tPA-dependent cell-surface plasminogen activation.\",\n      \"evidence\": \"MudPIT proteomics with carboxypeptidase B treatment, flow cytometry, co-localization, and plasminogen activation assay\",\n      \"pmids\": [\"19897580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement not yet demonstrated by genetic deletion\", \"Structural basis of Plg-RKT–plasminogen interaction unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the genetic basis of hypoplasminogenemia, novel PLG mutations (C166Y, Y264S, IVS10-7T/G) in homozygous or compound-heterozygous states were confirmed to cause ligneous conjunctivitis, periodontitis, hydrocephalus, and other mucosal fibrin-deposition phenotypes.\",\n      \"evidence\": \"Sanger sequencing and molecular genetic analysis of 23 patients with clinical phenotyping\",\n      \"pmids\": [\"21174000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional characterization of individual mutations (e.g., folding, secretion, activation kinetics) not performed\", \"Genotype–phenotype correlations for severity not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic and antibody-blockade experiments established that Plg-RKT is required for macrophage chemotactic migration, Matrigel invasion, and peritoneal recruitment in a strictly plasminogen-dependent manner, and additionally regulates catecholamine secretion by chromaffin cells through plasmin-mediated prohormone processing.\",\n      \"evidence\": \"Anti-Plg-RKT mAb blockade in migration/invasion/peritonitis assays; plasminogen-null mice epistasis; overexpression and antibody studies in chromaffin/PC12 cells with norepinephrine secretion measurement\",\n      \"pmids\": [\"21940822\", \"21795689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plg-RKT genetic knockout phenotype not yet available at this time\", \"Prohormone substrates of plasmin on chromaffin cells not fully identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic deletion of Plg-RKT confirmed its non-redundant role in macrophage plasminogen binding and migration in vivo, and revealed an unexpected requirement for lactation, as all pups from Plg-RKT−/− dams died within 48 hours of birth.\",\n      \"evidence\": \"Plg-RKT knockout mice with macrophage binding assay, peritonitis model, and lactation phenotyping\",\n      \"pmids\": [\"27714956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of lactation failure (fibrinolytic vs. non-fibrinolytic) not resolved\", \"Plg-RKT contribution to other tissue-specific plasminogen functions unexplored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of the K330E kringle 3 missense mutation in families with hereditary angioedema and normal C1-inhibitor established a gain-of-function PLG mechanism as a novel cause of this disease.\",\n      \"evidence\": \"Whole-exome sequencing, Sanger validation, and autosomal dominant segregation in multiple families\",\n      \"pmids\": [\"28795768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of K330E gain-of-function (e.g., enhanced activation, altered binding) not characterized\", \"Therapeutic implications not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissecting the lactation failure mechanism, Plg-RKT−/− mammary glands showed blocked lobuloalveolar development with fibrotic stroma, massive fibrin deposition, macrophage infiltration, EGF downregulation, and increased apoptosis; however, fibrinogen heterozygosity did not rescue the phenotype, indicating contributions beyond fibrinolysis.\",\n      \"evidence\": \"Plg-RKT−/− and compound Plg-RKT−/−;Fib+/− knockout mammary gland analysis with IHC, proliferation, apoptosis, and transcriptional profiling\",\n      \"pmids\": [\"29495105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plasminogen-independent Plg-RKT functions in mammary development not molecularly defined\", \"Whether EGF downregulation is cause or consequence not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistic studies revealed that plasminogen and plasmin promote M2-like macrophage polarization and efferocytosis through STAT3 phosphorylation, and that Plg-RKT is selectively enriched on proinflammatory monocyte subsets whose directional migration is plasmin-dependent.\",\n      \"evidence\": \"Plg−/− and Plg-RKT−/− mouse pleurisy/peritonitis models, BMDM polarization with STAT3 western blot, flow cytometry for M1/M2 markers and Plg-RKT on monocyte subsets, multiple inhibitor strategies\",\n      \"pmids\": [\"31316511\", \"31221672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct STAT3 target genes mediating M2 polarization not identified\", \"Whether Plg-RKT signals independently of plasmin generation in polarization is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific knockouts showed that Plg-RKT in myeloid cells promotes wound healing through fibrin clearance and cytokine regulation, while keratinocyte-specific Plg-RKT deletion paradoxically accelerated healing with filaggrin upregulation, revealing opposing tissue-specific roles.\",\n      \"evidence\": \"Conditional Plg-RKT knockout mice (myeloid and keratinocyte-specific), burn wound model, fibrinogen compound knockouts, cytokine and transcriptional profiling\",\n      \"pmids\": [\"33311441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of keratinocyte Plg-RKT function (filaggrin regulation) not molecularly defined\", \"Whether findings generalize to other wound types unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending the Plg-RKT axis to platelets and new tissue contexts, activated platelets were shown to retain alpha-granule-secreted plasminogen on their surface via Plg-RKT to drive local fibrinolysis, while Plg-RKT−/− mice on high-fat diet developed adipose and hepatic inflammation, fibrosis, and insulin resistance with dysregulated PPARγ.\",\n      \"evidence\": \"Confocal microscopy, flow cytometry, and clot lysis assays on Plg-RKT−/− platelets; high-fat diet metabolic phenotyping with Plg-RKT−/− mice and adipocyte differentiation assays\",\n      \"pmids\": [\"32842150\", \"34897983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Plg-RKT to PPARγ regulation requires validation\", \"Whether platelet Plg-RKT is specifically required vs. other plasminogen receptors not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In liver fibrosis, Plg-RKT was identified as highly expressed on scar-associated macrophages, where plasminogen treatment drives SAM differentiation; selective Plg-RKT knockdown in intrahepatic macrophages reduced SAM numbers and alleviated fibrosis in two independent models.\",\n      \"evidence\": \"scRNA-seq, CyTOF, siRNA-GeRP-mediated macrophage-selective knockdown, BDL and CCl4 liver fibrosis models\",\n      \"pmids\": [\"37207518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plasmin-dependent versus plasmin-independent SAM differentiation mechanisms not dissected\", \"Translational potential in human liver fibrosis not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing a systemic endocrine role, liver-secreted plasminogen was shown to signal via Plg-RKT and ERK kinase on muscle satellite cells to promote their proliferation during caloric restriction, replicated in human CALERIE trial participants.\",\n      \"evidence\": \"MetRSL274G transgenic mouse liver secretome proteomics, plasminogen knockdown, Plg-RKT knockout, satellite cell quantification, ERK phosphorylation, human CALERIE cohort validation\",\n      \"pmids\": [\"38442019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether plasmin generation is required or Plg-RKT signals upon plasminogen binding not resolved\", \"Downstream ERK targets in satellite cells not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of Plg-RKT–plasminogen interaction, the biochemical mechanism of the K330E gain-of-function mutation in hereditary angioedema, whether Plg-RKT possesses plasmin-independent signaling capacity, and the relative contributions of plasminogen's fibrinolytic versus non-fibrinolytic functions in tissue-specific contexts such as mammary development, neurotrophin processing, and metabolic homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of Plg-RKT–plasminogen complex\", \"K330E biochemical mechanism uncharacterized\", \"Plasmin-independent Plg-RKT signaling not confirmed or excluded\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 9, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 7, 15, 30]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 16, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 3, 4, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 23, 24, 29]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 21, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLAT\",\n      \"PLAU\",\n      \"SERPINF2\",\n      \"ANXA2\",\n      \"PLGRKT\",\n      \"ENO1\",\n      \"AMOT\",\n      \"ATP5F1A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}