{"gene":"PLG","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"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, co-localizes with uPAR, interacts directly with tissue plasminogen activator, and markedly promotes cell surface plasminogen activation.","method":"Multidimensional protein identification technology (MudPIT) proteomics, carboxypeptidase B treatment, co-localization imaging, functional plasminogen activation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (proteomics discovery, biochemical activity assay, co-localization), replicated in subsequent studies","pmids":["19897580"],"is_preprint":false},{"year":2011,"finding":"Plg-RKT promotes plasminogen activation by urokinase-type plasminogen activator (uPA) on monocyte surfaces and is required for macrophage invasion through Matrigel, chemotactic migration, and macrophage recruitment in thioglycollate-induced peritonitis; anti-Plg-RKT antibody did not further reduce macrophage recruitment in plasminogen-null mice, placing Plg-RKT in the plasminogen-dependent pathway.","method":"Anti-Plg-RKT monoclonal antibody blockade, Matrigel invasion assay, chemotaxis assay, murine peritonitis model, plasminogen-null mouse epistasis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with plasminogen-null mice, multiple functional assays, replicated across labs","pmids":["21940822"],"is_preprint":false},{"year":2011,"finding":"Plg-RKT is expressed on the surface of catecholaminergic cells (adrenal chromaffin cells, PC12 cells), co-immunoprecipitates with uPAR, enhances plasminogen activation, and negatively regulates nicotine-evoked norepinephrine release; overexpression decreased norepinephrine release by 51% while antibody blockade increased it.","method":"GFP fusion localization, phase partitioning, co-immunoprecipitation with uPAR, FACS, stable overexpression, antibody blockade, neurosecretion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, overexpression, antibody blockade, functional secretion assay) in single study","pmids":["21795689"],"is_preprint":false},{"year":2016,"finding":"Genetic deletion of Plg-RKT in mice markedly decreased macrophage plasminogen binding capacity and macrophage recruitment in peritonitis; all offspring of Plg-RKT−/− females died within 2 days of birth, indicating Plg-RKT is required for lactation and species survival.","method":"Homologous recombination knockout mouse, peritonitis model, plasminogen binding assay, survival analysis of offspring","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular and organismal phenotypes, multiple readouts","pmids":["27714956"],"is_preprint":false},{"year":2018,"finding":"Plg-RKT is essential for mammary lobuloalveolar development and lactogenesis; Plg-RKT−/− glands showed fibrin accumulation in alveoli and ducts, hypertrophic fibrotic stroma, macrophage infiltration, 12-fold downregulation of EGF, absent epithelial cell proliferation, downregulated Mcl-1, and increased apoptosis. Fibrinogen heterozygosity decreased fibrin accumulation but did not rescue lobuloalveolar development defects.","method":"Knockout mouse model, histology, transcriptional profiling, fibrinogen genetic reduction cross, immunofluorescence, TUNEL assay","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal mechanistic readouts and genetic epistasis with fibrinogen","pmids":["29495105"],"is_preprint":false},{"year":2019,"finding":"Plasminogen (PLG) and plasmin (Pla) induced transient STAT3 phosphorylation and promoted M2-like macrophage polarization (increased CD206/Arginase-1, IL-10/TGF-β); Plg-RKT deletion impaired IL-4- and IL-10-induced STAT3 phosphorylation and M2 polarization, and decreased efferocytosis of apoptotic neutrophils in vivo and in vitro.","method":"Plg−/− and Plg-RKT−/− mouse models, BMDM culture, phospho-STAT3 western blot, flow cytometry, efferocytosis assay, murine pleurisy model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout models with multiple orthogonal biochemical and cellular assays","pmids":["31316511"],"is_preprint":false},{"year":2019,"finding":"Proinflammatory CD14++CD16+ human monocytes and Ly6Chigh mouse monocytes express the highest levels of Plg-RKT, bind more plasminogen, and their directional migration is plasmin-dependent and abolished by anti-Plg-RKT mAb, ε-aminocaproic acid, aprotinin, or the aminoterminal fragment of uPA; Plg-RKT−/− mice showed significantly reduced Ly6Chigh monocyte recruitment in peritonitis.","method":"Flow cytometry, anti-Plg-RKT mAb blockade, migration assay, Plg-RKT−/− mouse peritonitis model, immunohistochemistry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in vivo combined with multiple pharmacological inhibition methods and flow cytometric quantification","pmids":["31221672"],"is_preprint":false},{"year":2020,"finding":"Plg-RKT deletion delayed wound healing during the proliferation phase; fibrin clearance was significantly impaired in Plg-RKT−/− wound tissue; reducing fibrinogen levels 50% completely abrogated the wound healing delay, demonstrating that Plg-RKT's role in wound healing is fibrinogen/fibrin-dependent. Myeloid-specific Plg-RKT deletion delayed healing while keratinocyte-specific deletion accelerated it, with upregulation of filaggrin and caspase-14.","method":"Global and cell-type-specific conditional knockout mice, standardized burn wound model, fibrinogen genetic reduction, fibrin immunostaining, cytokine measurement","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional knockouts with genetic fibrinogen epistasis and multiple mechanistic readouts","pmids":["33311441"],"is_preprint":false},{"year":2021,"finding":"Plg-RKT is present in platelet membranes (17-kDa band by western blot) and co-localizes with platelet-derived plasminogen on activated platelet surfaces; Plg-RKT−/− platelets show significantly attenuated plasminogen exposure upon activation; platelet-derived plasminogen is retained on the activated platelet membrane via a lysine-dependent mechanism and drives local fibrinolysis.","method":"Western blotting, confocal microscopy, flow cytometry, Plg-RKT−/− mice, ε-aminocaproic acid treatment, fluorescent fibrin clot lysis assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal methods confirming receptor function and plasminogen retention","pmids":["32842150"],"is_preprint":false},{"year":2021,"finding":"Plg-RKT−/− mice fed a high-fat diet gained more weight, developed more hepatic steatosis, and were more insulin resistant/glucose intolerant than controls; mechanistically linked to increased adipose tissue inflammation, macrophage/T-cell accumulation, adipose and hepatic fibrosis, decreased insulin signaling, and reduced PPARγ expression. Plg-RKT levels dramatically increase during adipogenesis in 3T3-L1 cells.","method":"Plg-RKT−/− mouse HFD model, glucose/insulin tolerance tests, 3T3-L1 adipogenesis, immunofluorescence, RT-PCR, western blot","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined metabolic phenotype, but pathway placement (PPARγ) based on expression, single lab","pmids":["34897983"],"is_preprint":false},{"year":2023,"finding":"PLG signaling through Plg-RKT drives phenotypic transformation of scar-associated macrophages (SAMs) in liver fibrosis; in vitro, PLG-treated bone marrow macrophages adopted a SAM gene expression profile, and knockdown of Plg-RKT blocked this effect; selective Plg-RKT knockdown in intrahepatic macrophages in vivo reduced SAM numbers and alleviated BDL- and CCl4-induced liver fibrosis.","method":"scRNA-seq, CyTOF, siRNA-GeRP macrophage-selective knockdown, BDL and CCl4 mouse fibrosis models, in vitro BMM treatment with PLG","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo selective knockdown with two independent fibrosis models, in vitro mechanistic confirmation, single lab","pmids":["37207518"],"is_preprint":false},{"year":2024,"finding":"Liver-secreted plasminogen is required for muscle satellite cell (SC) expansion during caloric restriction; knockdown of circulating plasminogen prevents SC expansion; loss of Plg-RKT is sufficient to prevent CR-related SC expansion, consistent with direct signaling of plasminogen through Plg-RKT/ERK kinase to promote SC proliferation.","method":"MetRSL274G transgenic mouse (non-canonical amino acid labeling of liver secretome), plasminogen knockdown, Plg-RKT−/− mice, ERK signaling assay, CALERIE human trial replication","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown of circulating plasminogen plus Plg-RKT KO with defined proliferation phenotype, replicated in human participants","pmids":["38442019"],"is_preprint":false},{"year":1988,"finding":"Genetic linkage analysis established that the LP locus (determining Lp(a) lipoprotein levels) is linked to the PLG locus (peak lod score = 12.73), assigning both to chromosome 6q.","method":"Family-based linkage analysis, lod score calculation","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic linkage is well-replicated but is a genomic/positional finding rather than a direct mechanistic assay of PLG protein function","pmids":["2966760"],"is_preprint":false},{"year":2021,"finding":"PLG silencing in HBV-positive HCC cells promoted apoptosis and suppressed xenograft tumor growth in vivo through inhibiting HBV replication; SRC was identified as a downstream target upregulated by PLG, and PLG was proposed to promote HCC progression by activating the SRC-Hippo signaling axis.","method":"siRNA knockdown, qRT-PCR, western blot, ELISA, flow cytometry, TUNEL assay, subcutaneous xenograft model","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement of PLG→SRC→Hippo is inferred from differential expression after knockdown without direct binding or enzymatic validation","pmids":["33594307"],"is_preprint":false}],"current_model":"PLG (plasminogen) is the zymogen of the serine protease plasmin; its activation is markedly enhanced when it binds to cell surfaces via the transmembrane receptor Plg-RKT (which exposes a C-terminal lysine), where it physically associates with uPAR to concentrate plasminogen activation by tPA and uPA, thereby arming cells with broad-spectrum proteolytic activity that drives macrophage recruitment and migration, inflammation resolution through STAT3-mediated M2 polarization and efferocytosis, fibrin clearance during wound healing, platelet surface fibrinolysis, mammary lobuloalveolar development, muscle satellite cell expansion during caloric restriction via ERK signaling, and metabolic homeostasis through regulation of adipogenesis and PPARγ expression."},"narrative":{"mechanistic_narrative":"PLG (plasminogen) is the circulating zymogen whose surface-localized activation arms cells with broad-spectrum proteolytic activity that drives inflammatory cell trafficking, fibrin clearance, and tissue remodeling [PMID:21940822, PMID:33311441]. A central determinant of this activity is the integral membrane plasminogen receptor Plg-RKT, which exposes a C-terminal lysine, co-localizes with uPAR, binds tissue plasminogen activator, and markedly accelerates cell-surface plasminogen activation [PMID:19897580]. Through this receptor, plasminogen activation by uPA on monocyte and macrophage surfaces supports chemotactic migration, Matrigel invasion, and recruitment in peritonitis, with the highest receptor expression on proinflammatory monocyte subsets and migration that is strictly plasmin-dependent [PMID:21940822, PMID:31221672]. Beyond proteolysis, plasmin/plasminogen acts as a signaling ligand: it induces transient STAT3 phosphorylation to promote M2-like macrophage polarization and efferocytosis [PMID:31316511], drives scar-associated macrophage transformation in liver fibrosis [PMID:37207518], and signals through Plg-RKT/ERK to promote muscle satellite cell expansion during caloric restriction [PMID:38442019]. The fibrin-clearing arm of this system is required for wound healing and platelet-surface fibrinolysis, both demonstrably fibrin/fibrinogen-dependent [PMID:33311441, PMID:32842150], and for mammary lobuloalveolar development and lactation, loss of which is lethal to nursing offspring [PMID:27714956, PMID:29495105]. Plg-RKT also restrains catecholamine secretion in chromaffin cells [PMID:21795689] and supports metabolic homeostasis, with its loss exacerbating diet-induced steatosis, insulin resistance, and reduced PPARγ expression [PMID:34897983]. Genetic linkage places the Lp(a)-determining LP locus at PLG on chromosome 6q [PMID:2966760].","teleology":[{"year":1988,"claim":"Before molecular dissection of plasminogen function, the genomic position of PLG was established, anchoring it to chromosome 6q and linking it to control of Lp(a) lipoprotein levels.","evidence":"Family-based linkage analysis with lod score calculation","pmids":["2966760"],"confidence":"Medium","gaps":["Positional/genomic finding, not a direct assay of PLG protein function","Does not establish a mechanism connecting PLG to Lp(a) regulation"]},{"year":2009,"claim":"It was unknown how plasminogen is concentrated and efficiently activated at cell surfaces; identification of Plg-RKT as an integral membrane receptor exposing a C-terminal lysine, co-localizing with uPAR and binding tPA, defined the molecular platform for surface plasminogen activation.","evidence":"MudPIT proteomics, carboxypeptidase B treatment, co-localization imaging, and plasminogen activation assay","pmids":["19897580"],"confidence":"High","gaps":["Receptor structure and stoichiometry with uPAR not defined","Direct binding mode of plasminogen to the exposed C-terminal lysine not structurally resolved"]},{"year":2011,"claim":"To test whether the receptor is functionally required for immune cell behavior, blockade and plasminogen-null epistasis showed Plg-RKT promotes uPA-driven activation and is required for macrophage invasion, migration, and recruitment within the plasminogen pathway.","evidence":"Anti-Plg-RKT mAb blockade, Matrigel invasion and chemotaxis assays, peritonitis model, and plasminogen-null mouse epistasis","pmids":["21940822"],"confidence":"High","gaps":["Proteolytic substrates cleaved during invasion not enumerated","Did not yet use a Plg-RKT knockout"]},{"year":2011,"claim":"Whether Plg-RKT acts beyond myeloid cells was addressed in catecholaminergic cells, where it associates with uPAR, enhances plasminogen activation, and negatively regulates nicotine-evoked norepinephrine release.","evidence":"GFP localization, Co-IP with uPAR, overexpression, antibody blockade, and neurosecretion assay in chromaffin/PC12 cells","pmids":["21795689"],"confidence":"High","gaps":["Mechanism linking surface proteolysis to suppressed secretion unresolved","Single cell-type study without in vivo confirmation"]},{"year":2016,"claim":"Pharmacological blockade left open the in vivo necessity of the receptor; germline deletion confirmed Plg-RKT is required for macrophage plasminogen binding and recruitment, and revealed an essential role in lactation as all offspring of knockout females died neonatally.","evidence":"Homologous recombination knockout mouse, peritonitis model, plasminogen binding assay, and offspring survival analysis","pmids":["27714956"],"confidence":"High","gaps":["Tissue basis of lactation failure not yet mechanistically dissected","Cell-autonomous versus systemic contributions not separated"]},{"year":2018,"claim":"The neonatal lethality was traced to a mammary developmental defect: Plg-RKT loss caused fibrin accumulation, fibrotic stroma, loss of epithelial proliferation, EGF and Mcl-1 downregulation, and apoptosis, with the developmental defect only partly attributable to fibrin.","evidence":"Knockout histology, transcriptional profiling, fibrinogen genetic reduction cross, immunofluorescence, and TUNEL","pmids":["29495105"],"confidence":"High","gaps":["Fibrin-independent component of the developmental defect remains mechanistically undefined","Direct link between plasmin proteolysis and EGF/Mcl-1 regulation not established"]},{"year":2019,"claim":"Whether plasminogen acts only as a protease or also as a signaling ligand was tested in macrophages: plasmin/plasminogen induced STAT3 phosphorylation and M2 polarization and supported efferocytosis, all dependent on Plg-RKT.","evidence":"Plg-/- and Plg-RKT-/- mice, BMDM culture, phospho-STAT3 blots, flow cytometry, efferocytosis assay, and pleurisy model","pmids":["31316511"],"confidence":"High","gaps":["Receptor coupling that triggers STAT3 phosphorylation not identified","Distinction between proteolytic and direct signaling contributions incomplete"]},{"year":2019,"claim":"To refine which cells the receptor serves, proinflammatory monocyte subsets were shown to express the most Plg-RKT, bind the most plasminogen, and migrate in a plasmin-dependent manner abolished by receptor blockade or protease inhibitors.","evidence":"Flow cytometry, anti-Plg-RKT mAb blockade, migration assays, knockout peritonitis model, and immunohistochemistry","pmids":["31221672"],"confidence":"High","gaps":["Transcriptional control of subset-specific Plg-RKT expression unknown","Pericellular substrates enabling directional migration not mapped"]},{"year":2020,"claim":"The role of the receptor in tissue repair was resolved with conditional knockouts: Plg-RKT promotes fibrin clearance during the wound proliferation phase in a fibrinogen-dependent manner, with opposing myeloid and keratinocyte contributions.","evidence":"Global and cell-type-specific knockouts, burn wound model, fibrinogen genetic reduction, fibrin immunostaining, and cytokine measurement","pmids":["33311441"],"confidence":"High","gaps":["Mechanism of the keratinocyte-specific acceleration (filaggrin/caspase-14) not fully explained","Interplay between myeloid and epithelial arms in intact wounds unresolved"]},{"year":2021,"claim":"Extending fibrinolysis to hemostatic surfaces, platelet-membrane Plg-RKT was shown to retain platelet-derived plasminogen on activated platelets via a lysine-dependent mechanism, driving local clot lysis.","evidence":"Western blot, confocal microscopy, flow cytometry, knockout platelets, aminocaproic acid, and fibrin clot lysis assay","pmids":["32842150"],"confidence":"High","gaps":["Contribution to in vivo thrombus resolution not quantified","Regulation of platelet-surface plasminogen activation timing unknown"]},{"year":2021,"claim":"Whether the system contributes to metabolic homeostasis was tested with high-fat-diet knockouts, revealing worsened steatosis, insulin resistance, adipose inflammation/fibrosis, and reduced PPARγ, with receptor levels rising during adipogenesis.","evidence":"Knockout HFD model, glucose/insulin tolerance tests, 3T3-L1 adipogenesis, immunofluorescence, RT-PCR, and western blot","pmids":["34897983"],"confidence":"Medium","gaps":["PPARγ placement inferred from expression, not direct regulation","Single-lab finding; causal mechanism linking receptor loss to insulin resistance not isolated"]},{"year":2023,"claim":"Plasminogen signaling was shown to instruct macrophage fate in fibrosis: PLG drove scar-associated macrophage transformation through Plg-RKT, and macrophage-selective receptor knockdown alleviated liver fibrosis.","evidence":"scRNA-seq, CyTOF, macrophage-selective siRNA-GeRP knockdown, BDL and CCl4 fibrosis models, and in vitro BMM PLG treatment","pmids":["37207518"],"confidence":"High","gaps":["Signaling pathway downstream of Plg-RKT in SAM transformation not mapped","Single-lab finding"]},{"year":2024,"claim":"A systemic endocrine role emerged: liver-secreted plasminogen signals through Plg-RKT/ERK to drive muscle satellite cell expansion during caloric restriction, linking circulating plasminogen to regenerative capacity.","evidence":"Liver-secretome labeling (MetRSL274G), plasminogen knockdown, knockout mice, ERK assay, and CALERIE human replication","pmids":["38442019"],"confidence":"High","gaps":["Direct receptor-to-ERK coupling not structurally defined","Whether plasmin proteolysis is required versus zymogen-level signaling unresolved"]},{"year":2021,"claim":"A candidate tumor-promoting role was proposed in HBV-positive HCC, where PLG silencing induced apoptosis and suppressed xenografts, with SRC-Hippo signaling implicated downstream.","evidence":"siRNA knockdown, qRT-PCR, western blot, ELISA, flow cytometry, TUNEL, and xenograft model","pmids":["33594307"],"confidence":"Low","gaps":["PLG→SRC→Hippo placement inferred from differential expression without direct binding or enzymatic validation","Single lab, not independently confirmed","No demonstration of a direct PLG-SRC interaction"]},{"year":null,"claim":"The molecular events coupling Plg-RKT-bound plasmin(ogen) to intracellular signaling cascades (STAT3, ERK, SRC-Hippo) remain undefined — it is unresolved how a surface protease/receptor pair transduces transcriptional and proliferative signals.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the Plg-RKT/uPAR/plasminogen assembly","Signal transduction mechanism from receptor to kinase activation unknown","Whether proteolytic activity is strictly required for each signaling output not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8,11]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,6,10]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["PLAUR","PLAT","PLAU"],"other_free_text":[]}},"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":118,"is_preprint":false},{"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":90,"is_preprint":false},{"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},{"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},{"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},{"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},{"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},{"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},{"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 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19146495","citation_count":5,"is_preprint":false},{"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},{"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47148,"output_tokens":3707,"usd":0.098525,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11518,"output_tokens":4819,"usd":0.089033,"stage2_stop_reason":"end_turn"},"total_usd":0.187558,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"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.\",\n      \"method\": \"Multidimensional protein identification technology (MudPIT) proteomics, carboxypeptidase B treatment, co-localization imaging, functional plasminogen activation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (proteomics discovery, biochemical activity assay, co-localization), replicated in subsequent studies\",\n      \"pmids\": [\"19897580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plg-RKT promotes plasminogen activation by urokinase-type plasminogen activator (uPA) on monocyte surfaces and is required for macrophage invasion through Matrigel, chemotactic migration, and macrophage recruitment in thioglycollate-induced peritonitis; anti-Plg-RKT antibody did not further reduce macrophage recruitment in plasminogen-null mice, placing Plg-RKT in the plasminogen-dependent pathway.\",\n      \"method\": \"Anti-Plg-RKT monoclonal antibody blockade, Matrigel invasion assay, chemotaxis assay, murine peritonitis model, plasminogen-null mouse epistasis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with plasminogen-null mice, multiple functional assays, replicated across labs\",\n      \"pmids\": [\"21940822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plg-RKT is expressed on the surface of catecholaminergic cells (adrenal chromaffin cells, PC12 cells), co-immunoprecipitates with uPAR, enhances plasminogen activation, and negatively regulates nicotine-evoked norepinephrine release; overexpression decreased norepinephrine release by 51% while antibody blockade increased it.\",\n      \"method\": \"GFP fusion localization, phase partitioning, co-immunoprecipitation with uPAR, FACS, stable overexpression, antibody blockade, neurosecretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, overexpression, antibody blockade, functional secretion assay) in single study\",\n      \"pmids\": [\"21795689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of Plg-RKT in mice markedly decreased macrophage plasminogen binding capacity and macrophage recruitment in peritonitis; all offspring of Plg-RKT−/− females died within 2 days of birth, indicating Plg-RKT is required for lactation and species survival.\",\n      \"method\": \"Homologous recombination knockout mouse, peritonitis model, plasminogen binding assay, survival analysis of offspring\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular and organismal phenotypes, multiple readouts\",\n      \"pmids\": [\"27714956\"],\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 in alveoli and ducts, hypertrophic fibrotic stroma, macrophage infiltration, 12-fold downregulation of EGF, absent epithelial cell proliferation, downregulated Mcl-1, and increased apoptosis. Fibrinogen heterozygosity decreased fibrin accumulation but did not rescue lobuloalveolar development defects.\",\n      \"method\": \"Knockout mouse model, histology, transcriptional profiling, fibrinogen genetic reduction cross, immunofluorescence, TUNEL assay\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal mechanistic readouts and genetic epistasis with fibrinogen\",\n      \"pmids\": [\"29495105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Plasminogen (PLG) and plasmin (Pla) induced transient STAT3 phosphorylation and promoted M2-like macrophage polarization (increased CD206/Arginase-1, IL-10/TGF-β); Plg-RKT deletion impaired IL-4- and IL-10-induced STAT3 phosphorylation and M2 polarization, and decreased efferocytosis of apoptotic neutrophils in vivo and in vitro.\",\n      \"method\": \"Plg−/− and Plg-RKT−/− mouse models, BMDM culture, phospho-STAT3 western blot, flow cytometry, efferocytosis assay, murine pleurisy model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout models with multiple orthogonal biochemical and cellular assays\",\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 more plasminogen, and their directional migration is plasmin-dependent and abolished by anti-Plg-RKT mAb, ε-aminocaproic acid, aprotinin, or the aminoterminal fragment of uPA; Plg-RKT−/− mice showed significantly reduced Ly6Chigh monocyte recruitment in peritonitis.\",\n      \"method\": \"Flow cytometry, anti-Plg-RKT mAb blockade, migration assay, Plg-RKT−/− mouse peritonitis model, immunohistochemistry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in vivo combined with multiple pharmacological inhibition methods and flow cytometric quantification\",\n      \"pmids\": [\"31221672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plg-RKT deletion delayed wound healing during the proliferation phase; fibrin clearance was significantly impaired in Plg-RKT−/− wound tissue; reducing fibrinogen levels 50% completely abrogated the wound healing delay, demonstrating that Plg-RKT's role in wound healing is fibrinogen/fibrin-dependent. Myeloid-specific Plg-RKT deletion delayed healing while keratinocyte-specific deletion accelerated it, with upregulation of filaggrin and caspase-14.\",\n      \"method\": \"Global and cell-type-specific conditional knockout mice, standardized burn wound model, fibrinogen genetic reduction, fibrin immunostaining, cytokine measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional knockouts with genetic fibrinogen epistasis and multiple mechanistic readouts\",\n      \"pmids\": [\"33311441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT is present in platelet membranes (17-kDa band by western blot) and co-localizes with platelet-derived plasminogen on activated platelet surfaces; Plg-RKT−/− platelets show significantly attenuated plasminogen exposure upon activation; platelet-derived plasminogen is retained on the activated platelet membrane via a lysine-dependent mechanism and drives local fibrinolysis.\",\n      \"method\": \"Western blotting, confocal microscopy, flow cytometry, Plg-RKT−/− mice, ε-aminocaproic acid treatment, fluorescent fibrin clot lysis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal methods confirming receptor function and plasminogen retention\",\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 controls; mechanistically linked to increased adipose tissue inflammation, macrophage/T-cell accumulation, adipose and hepatic fibrosis, decreased insulin signaling, and reduced PPARγ expression. Plg-RKT levels dramatically increase during adipogenesis in 3T3-L1 cells.\",\n      \"method\": \"Plg-RKT−/− mouse HFD model, glucose/insulin tolerance tests, 3T3-L1 adipogenesis, immunofluorescence, RT-PCR, western blot\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined metabolic phenotype, but pathway placement (PPARγ) based on expression, single lab\",\n      \"pmids\": [\"34897983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLG signaling through Plg-RKT drives phenotypic transformation of scar-associated macrophages (SAMs) in liver fibrosis; in vitro, PLG-treated bone marrow macrophages adopted a SAM gene expression profile, and knockdown of Plg-RKT blocked this effect; selective Plg-RKT knockdown in intrahepatic macrophages in vivo reduced SAM numbers and alleviated BDL- and CCl4-induced liver fibrosis.\",\n      \"method\": \"scRNA-seq, CyTOF, siRNA-GeRP macrophage-selective knockdown, BDL and CCl4 mouse fibrosis models, in vitro BMM treatment with PLG\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo selective knockdown with two independent fibrosis models, in vitro mechanistic confirmation, single lab\",\n      \"pmids\": [\"37207518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liver-secreted plasminogen is required for muscle satellite cell (SC) expansion during caloric restriction; knockdown of circulating plasminogen prevents SC expansion; loss of Plg-RKT is sufficient to prevent CR-related SC expansion, consistent with direct signaling of plasminogen through Plg-RKT/ERK kinase to promote SC proliferation.\",\n      \"method\": \"MetRSL274G transgenic mouse (non-canonical amino acid labeling of liver secretome), plasminogen knockdown, Plg-RKT−/− mice, ERK signaling assay, CALERIE human trial replication\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown of circulating plasminogen plus Plg-RKT KO with defined proliferation phenotype, replicated in human participants\",\n      \"pmids\": [\"38442019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Genetic linkage analysis established that the LP locus (determining Lp(a) lipoprotein levels) is linked to the PLG locus (peak lod score = 12.73), assigning both to chromosome 6q.\",\n      \"method\": \"Family-based linkage analysis, lod score calculation\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic linkage is well-replicated but is a genomic/positional finding rather than a direct mechanistic assay of PLG protein function\",\n      \"pmids\": [\"2966760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLG silencing in HBV-positive HCC cells promoted apoptosis and suppressed xenograft tumor growth in vivo through inhibiting HBV replication; SRC was identified as a downstream target upregulated by PLG, and PLG was proposed to promote HCC progression by activating the SRC-Hippo signaling axis.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, western blot, ELISA, flow cytometry, TUNEL assay, subcutaneous xenograft model\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement of PLG→SRC→Hippo is inferred from differential expression after knockdown without direct binding or enzymatic validation\",\n      \"pmids\": [\"33594307\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLG (plasminogen) is the zymogen of the serine protease plasmin; its activation is markedly enhanced when it binds to cell surfaces via the transmembrane receptor Plg-RKT (which exposes a C-terminal lysine), where it physically associates with uPAR to concentrate plasminogen activation by tPA and uPA, thereby arming cells with broad-spectrum proteolytic activity that drives macrophage recruitment and migration, inflammation resolution through STAT3-mediated M2 polarization and efferocytosis, fibrin clearance during wound healing, platelet surface fibrinolysis, mammary lobuloalveolar development, muscle satellite cell expansion during caloric restriction via ERK signaling, and metabolic homeostasis through regulation of adipogenesis and PPARγ expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLG (plasminogen) is the circulating zymogen whose surface-localized activation arms cells with broad-spectrum proteolytic activity that drives inflammatory cell trafficking, fibrin clearance, and tissue remodeling [#1, #7]. A central determinant of this activity is the integral membrane plasminogen receptor Plg-RKT, which exposes a C-terminal lysine, co-localizes with uPAR, binds tissue plasminogen activator, and markedly accelerates cell-surface plasminogen activation [#0]. Through this receptor, plasminogen activation by uPA on monocyte and macrophage surfaces supports chemotactic migration, Matrigel invasion, and recruitment in peritonitis, with the highest receptor expression on proinflammatory monocyte subsets and migration that is strictly plasmin-dependent [#1, #6]. Beyond proteolysis, plasmin/plasminogen acts as a signaling ligand: it induces transient STAT3 phosphorylation to promote M2-like macrophage polarization and efferocytosis [#5], drives scar-associated macrophage transformation in liver fibrosis [#10], and signals through Plg-RKT/ERK to promote muscle satellite cell expansion during caloric restriction [#11]. The fibrin-clearing arm of this system is required for wound healing and platelet-surface fibrinolysis, both demonstrably fibrin/fibrinogen-dependent [#7, #8], and for mammary lobuloalveolar development and lactation, loss of which is lethal to nursing offspring [#3, #4]. Plg-RKT also restrains catecholamine secretion in chromaffin cells [#2] and supports metabolic homeostasis, with its loss exacerbating diet-induced steatosis, insulin resistance, and reduced PPARγ expression [#9]. Genetic linkage places the Lp(a)-determining LP locus at PLG on chromosome 6q [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Before molecular dissection of plasminogen function, the genomic position of PLG was established, anchoring it to chromosome 6q and linking it to control of Lp(a) lipoprotein levels.\",\n      \"evidence\": \"Family-based linkage analysis with lod score calculation\",\n      \"pmids\": [\"2966760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Positional/genomic finding, not a direct assay of PLG protein function\", \"Does not establish a mechanism connecting PLG to Lp(a) regulation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"It was unknown how plasminogen is concentrated and efficiently activated at cell surfaces; identification of Plg-RKT as an integral membrane receptor exposing a C-terminal lysine, co-localizing with uPAR and binding tPA, defined the molecular platform for surface plasminogen activation.\",\n      \"evidence\": \"MudPIT proteomics, carboxypeptidase B treatment, co-localization imaging, and plasminogen activation assay\",\n      \"pmids\": [\"19897580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor structure and stoichiometry with uPAR not defined\", \"Direct binding mode of plasminogen to the exposed C-terminal lysine not structurally resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"To test whether the receptor is functionally required for immune cell behavior, blockade and plasminogen-null epistasis showed Plg-RKT promotes uPA-driven activation and is required for macrophage invasion, migration, and recruitment within the plasminogen pathway.\",\n      \"evidence\": \"Anti-Plg-RKT mAb blockade, Matrigel invasion and chemotaxis assays, peritonitis model, and plasminogen-null mouse epistasis\",\n      \"pmids\": [\"21940822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proteolytic substrates cleaved during invasion not enumerated\", \"Did not yet use a Plg-RKT knockout\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether Plg-RKT acts beyond myeloid cells was addressed in catecholaminergic cells, where it associates with uPAR, enhances plasminogen activation, and negatively regulates nicotine-evoked norepinephrine release.\",\n      \"evidence\": \"GFP localization, Co-IP with uPAR, overexpression, antibody blockade, and neurosecretion assay in chromaffin/PC12 cells\",\n      \"pmids\": [\"21795689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking surface proteolysis to suppressed secretion unresolved\", \"Single cell-type study without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pharmacological blockade left open the in vivo necessity of the receptor; germline deletion confirmed Plg-RKT is required for macrophage plasminogen binding and recruitment, and revealed an essential role in lactation as all offspring of knockout females died neonatally.\",\n      \"evidence\": \"Homologous recombination knockout mouse, peritonitis model, plasminogen binding assay, and offspring survival analysis\",\n      \"pmids\": [\"27714956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue basis of lactation failure not yet mechanistically dissected\", \"Cell-autonomous versus systemic contributions not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The neonatal lethality was traced to a mammary developmental defect: Plg-RKT loss caused fibrin accumulation, fibrotic stroma, loss of epithelial proliferation, EGF and Mcl-1 downregulation, and apoptosis, with the developmental defect only partly attributable to fibrin.\",\n      \"evidence\": \"Knockout histology, transcriptional profiling, fibrinogen genetic reduction cross, immunofluorescence, and TUNEL\",\n      \"pmids\": [\"29495105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fibrin-independent component of the developmental defect remains mechanistically undefined\", \"Direct link between plasmin proteolysis and EGF/Mcl-1 regulation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether plasminogen acts only as a protease or also as a signaling ligand was tested in macrophages: plasmin/plasminogen induced STAT3 phosphorylation and M2 polarization and supported efferocytosis, all dependent on Plg-RKT.\",\n      \"evidence\": \"Plg-/- and Plg-RKT-/- mice, BMDM culture, phospho-STAT3 blots, flow cytometry, efferocytosis assay, and pleurisy model\",\n      \"pmids\": [\"31316511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling that triggers STAT3 phosphorylation not identified\", \"Distinction between proteolytic and direct signaling contributions incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To refine which cells the receptor serves, proinflammatory monocyte subsets were shown to express the most Plg-RKT, bind the most plasminogen, and migrate in a plasmin-dependent manner abolished by receptor blockade or protease inhibitors.\",\n      \"evidence\": \"Flow cytometry, anti-Plg-RKT mAb blockade, migration assays, knockout peritonitis model, and immunohistochemistry\",\n      \"pmids\": [\"31221672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional control of subset-specific Plg-RKT expression unknown\", \"Pericellular substrates enabling directional migration not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The role of the receptor in tissue repair was resolved with conditional knockouts: Plg-RKT promotes fibrin clearance during the wound proliferation phase in a fibrinogen-dependent manner, with opposing myeloid and keratinocyte contributions.\",\n      \"evidence\": \"Global and cell-type-specific knockouts, burn wound model, fibrinogen genetic reduction, fibrin immunostaining, and cytokine measurement\",\n      \"pmids\": [\"33311441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of the keratinocyte-specific acceleration (filaggrin/caspase-14) not fully explained\", \"Interplay between myeloid and epithelial arms in intact wounds unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending fibrinolysis to hemostatic surfaces, platelet-membrane Plg-RKT was shown to retain platelet-derived plasminogen on activated platelets via a lysine-dependent mechanism, driving local clot lysis.\",\n      \"evidence\": \"Western blot, confocal microscopy, flow cytometry, knockout platelets, aminocaproic acid, and fibrin clot lysis assay\",\n      \"pmids\": [\"32842150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution to in vivo thrombus resolution not quantified\", \"Regulation of platelet-surface plasminogen activation timing unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether the system contributes to metabolic homeostasis was tested with high-fat-diet knockouts, revealing worsened steatosis, insulin resistance, adipose inflammation/fibrosis, and reduced PPARγ, with receptor levels rising during adipogenesis.\",\n      \"evidence\": \"Knockout HFD model, glucose/insulin tolerance tests, 3T3-L1 adipogenesis, immunofluorescence, RT-PCR, and western blot\",\n      \"pmids\": [\"34897983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PPARγ placement inferred from expression, not direct regulation\", \"Single-lab finding; causal mechanism linking receptor loss to insulin resistance not isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Plasminogen signaling was shown to instruct macrophage fate in fibrosis: PLG drove scar-associated macrophage transformation through Plg-RKT, and macrophage-selective receptor knockdown alleviated liver fibrosis.\",\n      \"evidence\": \"scRNA-seq, CyTOF, macrophage-selective siRNA-GeRP knockdown, BDL and CCl4 fibrosis models, and in vitro BMM PLG treatment\",\n      \"pmids\": [\"37207518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of Plg-RKT in SAM transformation not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A systemic endocrine role emerged: liver-secreted plasminogen signals through Plg-RKT/ERK to drive muscle satellite cell expansion during caloric restriction, linking circulating plasminogen to regenerative capacity.\",\n      \"evidence\": \"Liver-secretome labeling (MetRSL274G), plasminogen knockdown, knockout mice, ERK assay, and CALERIE human replication\",\n      \"pmids\": [\"38442019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor-to-ERK coupling not structurally defined\", \"Whether plasmin proteolysis is required versus zymogen-level signaling unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A candidate tumor-promoting role was proposed in HBV-positive HCC, where PLG silencing induced apoptosis and suppressed xenografts, with SRC-Hippo signaling implicated downstream.\",\n      \"evidence\": \"siRNA knockdown, qRT-PCR, western blot, ELISA, flow cytometry, TUNEL, and xenograft model\",\n      \"pmids\": [\"33594307\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PLG→SRC→Hippo placement inferred from differential expression without direct binding or enzymatic validation\", \"Single lab, not independently confirmed\", \"No demonstration of a direct PLG-SRC interaction\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular events coupling Plg-RKT-bound plasmin(ogen) to intracellular signaling cascades (STAT3, ERK, SRC-Hippo) remain undefined — it is unresolved how a surface protease/receptor pair transduces transcriptional and proliferative signals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the Plg-RKT/uPAR/plasminogen assembly\", \"Signal transduction mechanism from receptor to kinase activation unknown\", \"Whether proteolytic activity is strictly required for each signaling output not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 6, 10]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLAUR\", \"PLAT\", \"PLAU\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}