{"gene":"PLGRKT","run_date":"2026-04-28T19:45:44","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, binds plasminogen, and markedly promotes cell surface plasminogen activation. It was found to co-localize with uPAR on the cell surface and to interact directly with tissue plasminogen activator.","method":"MudPIT proteomics, carboxypeptidase B-sensitive binding assays, co-localization imaging, cell surface plasminogen activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — original discovery using multiple orthogonal methods (proteomics, binding assays, functional activation assays, imaging); highly cited foundational paper","pmids":["19897580"],"is_preprint":false},{"year":2011,"finding":"Plg-RKT is expressed on the surface of catecholaminergic cells, co-immunoprecipitates with uPAR, localizes to the plasma membrane (GFP-fusion and FACS with C-terminal antibody), enhances plasminogen activation, and negatively regulates nicotine-evoked catecholamine (norepinephrine) release through plasmin-mediated prohormone cleavage.","method":"Co-immunoprecipitation with uPAR, GFP-fusion localization, FACS, stable overexpression plasminogen activation assays, antibody blockade, [3H]norepinephrine secretion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, localization, gain-of-function, loss-of-function with antibody blockade, functional secretion assay) in a single study","pmids":["21795689"],"is_preprint":false},{"year":2016,"finding":"Genetic deletion of Plg-RKT in mice causes a marked defect in macrophage plasminogen binding and macrophage recruitment in experimental peritonitis in vivo, establishing Plg-RKT as a required plasminogen receptor for macrophage migration. Additionally, Plg-RKT-/- female mice exhibit lactation failure causing death of all offspring.","method":"Homologous recombination knockout mice, peritonitis model, plasminogen binding assays on Plg-RKT-/- macrophages, lactation phenotype analysis","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular phenotype (plasminogen binding, macrophage recruitment, lactation failure) replicated across multiple assays","pmids":["27714956"],"is_preprint":false},{"year":2016,"finding":"PlgRKT mediates endocytosis of Lp(a) in liver cells; knockout reduces Lp(a) internalization ~3-fold and overexpression increases it ~2-fold. After internalization, the apo(a) component is recycled via Rab5 early endosomes, trans-Golgi network, and Rab11 recycling endosomes, while the LDL component is degraded in lysosomes.","method":"PlgRKT knockout and overexpression in HAP1 and hepatoma cells, Western blot, confocal microscopy with organelle markers (Rab5, Rab11), flow cytometry","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal KO and OE with defined molecular phenotype, multiple cell lines, orthogonal imaging and biochemical methods","pmids":["28003220"],"is_preprint":false},{"year":2018,"finding":"Plg-RKT is essential for mammary lobuloalveolar development and lactation. In Plg-RKT-/- mice, lobuloalveolar development is blocked by hypertrophic fibrotic stroma, fibrin accumulates in alveoli/ducts, EGF is downregulated 12-fold, epithelial cell proliferation is absent, and Mcl-1 is downregulated with apoptosis observed. These defects are not rescued by fibrinogen heterozygosity, indicating plasminogen-independent mechanisms also contribute.","method":"Plg-RKT KO mice, fibrin immunostaining, macrophage infiltration analysis, transcriptional profiling, proliferation (Ki67), apoptosis assays, fibrinogen double-KO epistasis","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with detailed mechanistic dissection including epistasis (fibrinogen heterozygosity) and transcriptional profiling","pmids":["29495105"],"is_preprint":false},{"year":2019,"finding":"Plg-RKT and plasminogen regulate macrophage polarization: plasminogen/plasmin increases M2 markers (CD206, Arginase-1, IL-10, TGF-β) and decreases M1 markers; Plg-RKT-/- macrophages show defective IL-4-induced M2 polarization linked to decreased STAT3 phosphorylation. Plg-RKT and plasminogen are required for efferocytosis (phagocytosis of apoptotic neutrophils) in vivo and in vitro.","method":"Plg-RKT-/- and Plg-/- mouse bone-marrow-derived macrophages, flow cytometry, ELISA, Western blot for STAT3 phosphorylation, in vivo/in vitro efferocytosis assays, murine pleurisy model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple mechanistic readouts (STAT3 signaling, efferocytosis, polarization markers) in vivo and in vitro","pmids":["31316511"],"is_preprint":false},{"year":2019,"finding":"Plg-RKT is differentially expressed on proinflammatory monocyte/macrophage subsets (CD14++CD16+ human monocytes, Ly6Chigh mouse monocytes), which bind more plasminogen and exhibit plasmin-dependent directional migration. Anti-Plg-RKT antibody abolishes this migration. In vivo, Plg-RKT-/- mice show reduced Ly6Chigh monocyte recruitment in peritonitis.","method":"Flow cytometry, anti-Plg-RKT antibody blockade of migration, plasminogen binding assays, Plg-RKT-/- mice peritonitis model, immunohistochemistry of human plaques","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — antibody blockade, KO mice in vivo model, and multiple cell-type analyses providing convergent mechanistic evidence","pmids":["31221672"],"is_preprint":false},{"year":2020,"finding":"Plg-RKT deletion in mice impairs fibrin clearance in cutaneous burn wounds (fibrinogen heterozygosity rescues wound healing delay), dysregulates inflammatory cytokine expression, and paradoxically accelerates wound closure when deleted specifically in keratinocytes (associated with upregulation of filaggrin and caspase 14). Myeloid cell-specific Plg-RKT deletion delays healing.","method":"Plg-RKT global and cell-type-specific (myeloid, keratinocyte) KO mice, burn wound model, fibrinogen epistasis (double KO), gene expression profiling, wound closure quantification","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with epistasis experiments and mechanistic gene expression analysis","pmids":["33311441"],"is_preprint":false},{"year":2021,"finding":"Plg-RKT is expressed in platelet membranes and, upon platelet activation, co-localizes with platelet-derived plasminogen on the membrane surface in a lysine-dependent manner. Plg-RKT-/- platelets show attenuated plasminogen surface exposure after activation. Platelet Plg-RKT drives local fibrinolysis by enhancing cell surface plasminogen activation.","method":"Western blotting (platelet membrane fractions), confocal microscopy, flow cytometry, Plg-RKT-/- mice, plasminogen-/- platelets, fibrinolysis assays (fluorescent clot, turbidimetry), ε-aminocaproic acid competition","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including KO comparison, lysine-analog competition, and functional fibrinolysis assays","pmids":["32842150"],"is_preprint":false},{"year":2021,"finding":"Plg-RKT deficiency in mice fed a high-fat diet leads to worsened metabolic dysfunction (increased weight gain, hepatic steatosis, insulin resistance), increased adipose inflammation and fibrosis, and impaired adipogenesis. Plg-RKT regulates expression of PPARγ and other adipogenic molecules, suggesting a role in the adipogenic program.","method":"Plg-RKT-/- mice on HFD, glucose/insulin tolerance tests, adipose histology, macrophage/T-cell quantification, 3T3-L1 and primary preadipocyte cultures, RT-PCR for PPARγ and adipogenic genes","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with metabolic phenotyping, but adipogenic mechanism is correlative (gene expression) rather than direct biochemical demonstration","pmids":["34897983"],"is_preprint":false},{"year":2024,"finding":"Liver-secreted plasminogen signals through Plg-RKT on muscle satellite cells to promote their proliferation via ERK kinase during caloric restriction. Loss of circulating plasminogen (knockdown) or Plg-RKT prevents caloric restriction-induced satellite cell expansion.","method":"MetRSL274G transgenic mouse proteomics to identify liver-secreted plasminogen, plasminogen knockdown, Plg-RKT-/- mice, satellite cell quantification, ERK signaling measurement, human CALERIE trial replication","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and knockdown with defined signaling pathway (Plg-RKT/ERK), replicated in human cohort, but ERK pathway assignment is based on correlation rather than direct in vitro reconstitution","pmids":["38442019"],"is_preprint":false},{"year":2025,"finding":"Macrophage-specific Plg-RKT deletion protects mice from HFD-induced obesity and MASLD. Mechanistically, mPlg-RKT deficiency reduces hepatic Akt activation, lowers fatty acid synthase expression, activates PPARα fatty acid oxidation, and shifts adipose macrophage polarization from M1 to M2, enhancing insulin sensitivity and reducing plasma free fatty acids available for liver uptake. Hepatocyte-specific Plg-RKT deletion does not confer this protection.","method":"Macrophage- and hepatocyte-specific conditional KO mice on HFD, RNA sequencing, Akt and FAS Western blotting, PPARα pathway analysis, adipose macrophage flow cytometry, metabolic phenotyping","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with epistatic comparison (macrophage vs hepatocyte KO), RNA-seq, and multiple mechanistic biochemical readouts","pmids":["41077131"],"is_preprint":false}],"current_model":"PLGRKT (Plg-RKT) is a structurally unique integral transmembrane plasminogen receptor that exposes a C-terminal lysine on the extracellular face of the cell, tethering plasminogen to the cell surface and promoting its activation to plasmin by both tPA and uPA through physical association with uPAR; this plasmin activity drives macrophage recruitment and migration, macrophage polarization toward M2 phenotype via STAT3 signaling, efferocytosis, fibrinolysis in wounds and on activated platelets, catecholamine release regulation in chromaffin cells, satellite cell proliferation via ERK signaling during caloric restriction, and Lp(a) endocytosis/recycling in hepatocytes, while also regulating mammary lobuloalveolar development and adipose metabolic homeostasis through both plasminogen-dependent and -independent mechanisms."},"narrative":{"teleology":[{"year":2009,"claim":"The identity of a transmembrane plasminogen receptor exposing a C-terminal lysine was unknown; proteomic discovery of Plg-RKT established it as a novel integral membrane receptor that co-localizes with uPAR and directly enhances cell-surface plasminogen activation, defining the founding molecular mechanism.","evidence":"MudPIT proteomics, carboxypeptidase B-sensitive binding assays, co-localization imaging, and plasminogen activation assays in monocytoid cells","pmids":["19897580"],"confidence":"High","gaps":["Three-dimensional structure and topology of the transmembrane domain not resolved","Stoichiometry of Plg-RKT/uPAR complex not determined","Whether Plg-RKT has functions independent of plasminogen binding was unknown"]},{"year":2011,"claim":"Whether Plg-RKT physically associates with uPAR and has functional consequences beyond plasminogen binding was unclear; co-immunoprecipitation confirmed a direct uPAR interaction and functional assays showed Plg-RKT negatively regulates nicotine-evoked catecholamine release through plasmin-mediated prohormone processing, extending its role to neuroendocrine secretion.","evidence":"Co-IP with uPAR, GFP-fusion plasma membrane localization, FACS, overexpression plasminogen activation assays, antibody blockade, [³H]norepinephrine secretion in catecholaminergic cells","pmids":["21795689"],"confidence":"High","gaps":["Whether catecholamine regulation is relevant in vivo not tested","Identity of prohormone substrates cleaved by Plg-RKT-generated plasmin not defined"]},{"year":2016,"claim":"The in vivo requirement of Plg-RKT for plasminogen-dependent cell migration and tissue-level physiology was unproven; global knockout mice demonstrated that Plg-RKT is essential for macrophage plasminogen binding and recruitment in peritonitis and for mammary function (lactation failure), establishing it as a non-redundant plasminogen receptor in vivo.","evidence":"Homologous recombination KO mice, peritonitis model, plasminogen binding on KO macrophages, lactation phenotype","pmids":["27714956"],"confidence":"High","gaps":["Cell-type-specific contributions (myeloid vs. epithelial) not dissected","Whether lactation failure is plasminogen-dependent or -independent was unknown"]},{"year":2016,"claim":"Whether Plg-RKT mediates lipoprotein uptake was unknown; KO and overexpression studies showed it is a receptor for Lp(a) endocytosis in hepatocytes, with apo(a) recycled through Rab5/Rab11 endosomal compartments and LDL degraded in lysosomes, revealing a distinct endocytic trafficking function.","evidence":"PlgRKT KO and OE in HAP1 and hepatoma cells, confocal microscopy with Rab5/Rab11 markers, flow cytometry, Western blot","pmids":["28003220"],"confidence":"High","gaps":["Whether Lp(a) endocytosis requires plasminogen co-binding not tested","Structural basis for Lp(a) recognition not determined","In vivo hepatic Lp(a) clearance in KO mice not reported"]},{"year":2018,"claim":"Whether the lactation defect was purely fibrinolytic was untested; fibrinogen epistasis showed that lobuloalveolar developmental failure involves plasminogen-independent mechanisms (EGF downregulation, Mcl-1 loss, absent epithelial proliferation, stromal fibrosis), demonstrating Plg-RKT has functions beyond fibrin clearance.","evidence":"Plg-RKT KO mice, fibrin staining, fibrinogen double-KO epistasis, Ki67/apoptosis assays, transcriptional profiling of mammary gland","pmids":["29495105"],"confidence":"High","gaps":["Direct molecular target mediating EGF regulation not identified","Whether Plg-RKT signals independently of plasmin generation not biochemically demonstrated"]},{"year":2019,"claim":"The downstream signaling through which Plg-RKT shapes macrophage phenotype was unknown; KO macrophages revealed that Plg-RKT and plasminogen drive M2 polarization via STAT3 phosphorylation and are required for efferocytosis, linking the receptor to resolution of inflammation.","evidence":"Plg-RKT−/− and Plg−/− BMDMs, STAT3 phosphorylation Western blot, flow cytometry for CD206/Arg-1, in vivo/in vitro efferocytosis, murine pleurisy model","pmids":["31316511"],"confidence":"High","gaps":["How plasmin activates STAT3 (direct vs. indirect receptor signaling) not resolved","Whether efferocytosis defect is purely polarization-dependent or involves separate adhesion mechanism unknown"]},{"year":2019,"claim":"Which monocyte subsets depend on Plg-RKT for migration was unresolved; differential expression on proinflammatory CD14++CD16+ (human) and Ly6Chigh (mouse) monocytes and antibody blockade showed Plg-RKT is selectively required for plasmin-dependent directional migration of inflammatory monocyte subsets.","evidence":"Flow cytometry of monocyte subsets, anti-Plg-RKT antibody migration blockade, Plg-RKT−/− peritonitis, immunohistochemistry of human atherosclerotic plaques","pmids":["31221672"],"confidence":"High","gaps":["Mechanism regulating differential Plg-RKT surface expression across monocyte subsets not identified","Therapeutic relevance of blocking Plg-RKT in atherosclerosis not tested interventionally"]},{"year":2020,"claim":"Cell-type-specific roles of Plg-RKT in wound healing were undefined; conditional KO studies showed that myeloid Plg-RKT promotes fibrin clearance and wound repair (loss delays healing), while keratinocyte Plg-RKT paradoxically restrains wound closure (loss accelerates it via filaggrin/caspase-14 upregulation), revealing opposing tissue-specific functions.","evidence":"Global and cell-type-specific (myeloid, keratinocyte) KO mice, burn wound model, fibrinogen epistasis, gene expression profiling","pmids":["33311441"],"confidence":"High","gaps":["How keratinocyte Plg-RKT suppresses filaggrin/caspase-14 mechanistically not resolved","Whether keratinocyte phenotype is plasminogen-dependent not formally tested"]},{"year":2021,"claim":"Whether Plg-RKT functions on platelets was unknown; Plg-RKT was found in platelet membranes and shown to co-localize with platelet-derived plasminogen upon activation, driving local fibrinolysis in a lysine-dependent manner, establishing platelets as an autonomous fibrinolytic unit via Plg-RKT.","evidence":"Western blot of platelet membrane fractions, confocal microscopy, flow cytometry, Plg-RKT−/− and plasminogen−/− platelets, fluorescent clot and turbidimetric fibrinolysis assays, ε-aminocaproic acid competition","pmids":["32842150"],"confidence":"High","gaps":["Contribution of platelet Plg-RKT to in vivo thrombolysis not tested with platelet-specific KO","Whether platelet Plg-RKT influences thrombus stability under flow conditions unknown"]},{"year":2021,"claim":"Whether Plg-RKT regulates systemic metabolism was unexplored; global KO on high-fat diet revealed worsened obesity, insulin resistance, hepatic steatosis, and impaired adipogenesis linked to reduced PPARγ expression, suggesting a metabolic role beyond fibrinolysis.","evidence":"Plg-RKT−/− mice on HFD, glucose/insulin tolerance tests, adipose histology, 3T3-L1 and primary preadipocyte cultures, RT-PCR for PPARγ","pmids":["34897983"],"confidence":"Medium","gaps":["PPARγ regulation mechanism (direct transcriptional effect vs. indirect via plasmin) not established","Adipogenic phenotype not confirmed with adipocyte-specific conditional KO"]},{"year":2024,"claim":"Whether Plg-RKT transduces inter-organ endocrine signals was unknown; liver-secreted plasminogen was shown to signal through Plg-RKT on satellite cells to promote their proliferation via ERK during caloric restriction, establishing a hepatokine–receptor axis for muscle stem cell regulation.","evidence":"MetRSL274G transgenic proteomics, plasminogen knockdown, Plg-RKT−/− mice, satellite cell quantification, ERK measurement, human CALERIE trial replication","pmids":["38442019"],"confidence":"Medium","gaps":["Direct reconstitution of plasminogen/Plg-RKT/ERK signaling in isolated satellite cells not performed","Whether plasmin generation or intact plasminogen binding activates ERK not distinguished"]},{"year":2025,"claim":"Which cell type mediates Plg-RKT's metabolic protection was unresolved; macrophage-specific but not hepatocyte-specific deletion protected against HFD-induced obesity and MASLD by reducing hepatic Akt/FAS lipogenesis, activating PPARα oxidation, and shifting adipose macrophages toward M2, pinpointing macrophage Plg-RKT as the critical metabolic effector.","evidence":"Macrophage- and hepatocyte-specific conditional KO on HFD, RNA-seq, Akt/FAS Western blot, PPARα pathway analysis, adipose macrophage flow cytometry","pmids":["41077131"],"confidence":"High","gaps":["How macrophage Plg-RKT remotely regulates hepatic Akt remains mechanistically unclear","Whether the metabolic phenotype requires plasminogen not tested via epistasis with Plg KO"]},{"year":null,"claim":"Key open questions include: (1) the structural basis for Plg-RKT's C-terminal lysine exposure and uPAR interaction; (2) whether Plg-RKT transduces intracellular signals independently of plasmin generation; (3) the mechanism by which macrophage Plg-RKT remotely controls hepatic lipogenesis; and (4) whether Plg-RKT represents a viable therapeutic target for metabolic or fibrinolytic disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure available","Plasmin-independent signaling not biochemically reconstituted","Therapeutic targeting not explored in preclinical intervention studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,6,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3]}],"complexes":[],"partners":["PLAUR","PLAT","PLG"],"other_free_text":[]},"mechanistic_narrative":"PLGRKT (Plg-RKT) is an integral membrane plasminogen receptor that functions as a central organizer of cell-surface plasminogen activation, macrophage biology, fibrinolysis, and metabolic homeostasis. It exposes a C-terminal lysine on the extracellular face, directly binding plasminogen in a carboxypeptidase B-sensitive manner, co-localizing and interacting with uPAR and tPA to markedly enhance conversion of plasminogen to plasmin on the surfaces of monocytes/macrophages, platelets, and other cell types [PMID:19897580, PMID:32842150]. In macrophages, PLGRKT is required for plasminogen-dependent chemotactic migration, inflammatory recruitment, M2 polarization via STAT3 signaling, and efferocytosis; macrophage-specific deletion reshapes adipose inflammation and protects against diet-induced obesity and hepatic steatosis by shifting macrophage polarization, suppressing hepatic Akt/FAS lipogenesis, and activating PPARα-dependent fatty acid oxidation [PMID:31316511, PMID:31221672, PMID:41077131]. Beyond the immune compartment, PLGRKT drives mammary lobuloalveolar development through both fibrinolytic and plasminogen-independent mechanisms, mediates hepatic Lp(a) endocytosis and intracellular trafficking, regulates catecholamine secretion in chromaffin cells, promotes satellite cell proliferation via ERK signaling during caloric restriction, and supports fibrin clearance in wound healing [PMID:29495105, PMID:28003220, PMID:21795689, PMID:38442019, PMID:33311441]."},"prefetch_data":{"uniprot":{"accession":"Q9HBL7","full_name":"Plasminogen receptor (KT)","aliases":[],"length_aa":147,"mass_kda":17.2,"function":"Receptor for plasminogen. Regulates urokinase plasminogen activator-dependent and stimulates tissue-type plasminogen activator-dependent cell surface plasminogen activation. Proposed to be part of a local catecholaminergic cell plasminogen activation system that regulates neuroendocrine prohormone processing. Involved in regulation of inflammatory response; regulates monocyte chemotactic migration and matrix metalloproteinase activation, such as of MMP2 and MMP9","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9HBL7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLGRKT","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TOMM20A","stoichiometry":10.0},{"gene":"SEC23A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PLGRKT","total_profiled":1310},"omim":[{"mim_id":"618444","title":"PLASMINOGEN RECEPTOR WITH C-TERMINAL LYSINE; PLGRKT","url":"https://www.omim.org/entry/618444"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Mitochondria","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLGRKT"},"hgnc":{"alias_symbol":["MDS030","FLJ14688","AD025","Plg-RKT"],"prev_symbol":["C9orf46"]},"alphafold":{"accession":"Q9HBL7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBL7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBL7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBL7-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLGRKT","jax_strain_url":"https://www.jax.org/strain/search?query=PLGRKT"},"sequence":{"accession":"Q9HBL7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HBL7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HBL7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBL7"}},"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},{"pmid":"28003220","id":"PMC_28003220","title":"Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis of Lipoprotein(a).","date":"2016","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/28003220","citation_count":75,"is_preprint":false},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"pmid":"37642146","id":"PMC_37642146","title":"Overexpression of Plg-RKT protects against adipose dysfunction and dysregulation of glucose homeostasis in diet-induced obese mice.","date":"2023","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/37642146","citation_count":2,"is_preprint":false},{"pmid":"35383548","id":"PMC_35383548","title":"Successful lactation in Plgrkt-deficient female mice caused by a 1-bp deletion of exon4.","date":"2022","source":"The Journal of dairy research","url":"https://pubmed.ncbi.nlm.nih.gov/35383548","citation_count":0,"is_preprint":false},{"pmid":"41077131","id":"PMC_41077131","title":"Macrophage Plg-RKT expression promotes diet-induced obesity and metabolic dysfunction-associated steatotic liver disease.","date":"2025","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/41077131","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10916,"output_tokens":3502,"usd":0.042639},"stage2":{"model":"claude-opus-4-6","input_tokens":6876,"output_tokens":3760,"usd":0.19257},"total_usd":0.235209,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","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, binds plasminogen, and markedly promotes cell surface plasminogen activation. It was found to co-localize with uPAR on the cell surface and to interact directly with tissue plasminogen activator.\",\n      \"method\": \"MudPIT proteomics, carboxypeptidase B-sensitive binding assays, co-localization imaging, cell surface plasminogen activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original discovery using multiple orthogonal methods (proteomics, binding assays, functional activation assays, imaging); highly cited foundational paper\",\n      \"pmids\": [\"19897580\"],\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, localizes to the plasma membrane (GFP-fusion and FACS with C-terminal antibody), enhances plasminogen activation, and negatively regulates nicotine-evoked catecholamine (norepinephrine) release through plasmin-mediated prohormone cleavage.\",\n      \"method\": \"Co-immunoprecipitation with uPAR, GFP-fusion localization, FACS, stable overexpression plasminogen activation assays, antibody blockade, [3H]norepinephrine secretion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, localization, gain-of-function, loss-of-function with antibody blockade, functional secretion assay) 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 causes a marked defect in macrophage plasminogen binding and macrophage recruitment in experimental peritonitis in vivo, establishing Plg-RKT as a required plasminogen receptor for macrophage migration. Additionally, Plg-RKT-/- female mice exhibit lactation failure causing death of all offspring.\",\n      \"method\": \"Homologous recombination knockout mice, peritonitis model, plasminogen binding assays on Plg-RKT-/- macrophages, lactation phenotype analysis\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular phenotype (plasminogen binding, macrophage recruitment, lactation failure) replicated across multiple assays\",\n      \"pmids\": [\"27714956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PlgRKT mediates endocytosis of Lp(a) in liver cells; knockout reduces Lp(a) internalization ~3-fold and overexpression increases it ~2-fold. After internalization, the apo(a) component is recycled via Rab5 early endosomes, trans-Golgi network, and Rab11 recycling endosomes, while the LDL component is degraded in lysosomes.\",\n      \"method\": \"PlgRKT knockout and overexpression in HAP1 and hepatoma cells, Western blot, confocal microscopy with organelle markers (Rab5, Rab11), flow cytometry\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal KO and OE with defined molecular phenotype, multiple cell lines, orthogonal imaging and biochemical methods\",\n      \"pmids\": [\"28003220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plg-RKT is essential for mammary lobuloalveolar development and lactation. In Plg-RKT-/- mice, lobuloalveolar development is blocked by hypertrophic fibrotic stroma, fibrin accumulates in alveoli/ducts, EGF is downregulated 12-fold, epithelial cell proliferation is absent, and Mcl-1 is downregulated with apoptosis observed. These defects are not rescued by fibrinogen heterozygosity, indicating plasminogen-independent mechanisms also contribute.\",\n      \"method\": \"Plg-RKT KO mice, fibrin immunostaining, macrophage infiltration analysis, transcriptional profiling, proliferation (Ki67), apoptosis assays, fibrinogen double-KO epistasis\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with detailed mechanistic dissection including epistasis (fibrinogen heterozygosity) and transcriptional profiling\",\n      \"pmids\": [\"29495105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Plg-RKT and plasminogen regulate macrophage polarization: plasminogen/plasmin increases M2 markers (CD206, Arginase-1, IL-10, TGF-β) and decreases M1 markers; Plg-RKT-/- macrophages show defective IL-4-induced M2 polarization linked to decreased STAT3 phosphorylation. Plg-RKT and plasminogen are required for efferocytosis (phagocytosis of apoptotic neutrophils) in vivo and in vitro.\",\n      \"method\": \"Plg-RKT-/- and Plg-/- mouse bone-marrow-derived macrophages, flow cytometry, ELISA, Western blot for STAT3 phosphorylation, in vivo/in vitro efferocytosis assays, murine pleurisy model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple mechanistic readouts (STAT3 signaling, efferocytosis, polarization markers) in vivo and in vitro\",\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, Ly6Chigh mouse monocytes), which bind more plasminogen and exhibit plasmin-dependent directional migration. Anti-Plg-RKT antibody abolishes this migration. In vivo, Plg-RKT-/- mice show reduced Ly6Chigh monocyte recruitment in peritonitis.\",\n      \"method\": \"Flow cytometry, anti-Plg-RKT antibody blockade of migration, plasminogen binding assays, Plg-RKT-/- mice peritonitis model, immunohistochemistry of human plaques\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antibody blockade, KO mice in vivo model, and multiple cell-type analyses providing convergent mechanistic evidence\",\n      \"pmids\": [\"31221672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plg-RKT deletion in mice impairs fibrin clearance in cutaneous burn wounds (fibrinogen heterozygosity rescues wound healing delay), dysregulates inflammatory cytokine expression, and paradoxically accelerates wound closure when deleted specifically in keratinocytes (associated with upregulation of filaggrin and caspase 14). Myeloid cell-specific Plg-RKT deletion delays healing.\",\n      \"method\": \"Plg-RKT global and cell-type-specific (myeloid, keratinocyte) KO mice, burn wound model, fibrinogen epistasis (double KO), gene expression profiling, wound closure quantification\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with epistasis experiments and mechanistic gene expression analysis\",\n      \"pmids\": [\"33311441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT is expressed in platelet membranes and, upon platelet activation, co-localizes with platelet-derived plasminogen on the membrane surface in a lysine-dependent manner. Plg-RKT-/- platelets show attenuated plasminogen surface exposure after activation. Platelet Plg-RKT drives local fibrinolysis by enhancing cell surface plasminogen activation.\",\n      \"method\": \"Western blotting (platelet membrane fractions), confocal microscopy, flow cytometry, Plg-RKT-/- mice, plasminogen-/- platelets, fibrinolysis assays (fluorescent clot, turbidimetry), ε-aminocaproic acid competition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including KO comparison, lysine-analog competition, and functional fibrinolysis assays\",\n      \"pmids\": [\"32842150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plg-RKT deficiency in mice fed a high-fat diet leads to worsened metabolic dysfunction (increased weight gain, hepatic steatosis, insulin resistance), increased adipose inflammation and fibrosis, and impaired adipogenesis. Plg-RKT regulates expression of PPARγ and other adipogenic molecules, suggesting a role in the adipogenic program.\",\n      \"method\": \"Plg-RKT-/- mice on HFD, glucose/insulin tolerance tests, adipose histology, macrophage/T-cell quantification, 3T3-L1 and primary preadipocyte cultures, RT-PCR for PPARγ and adipogenic genes\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with metabolic phenotyping, but adipogenic mechanism is correlative (gene expression) rather than direct biochemical demonstration\",\n      \"pmids\": [\"34897983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liver-secreted plasminogen signals through Plg-RKT on muscle satellite cells to promote their proliferation via ERK kinase during caloric restriction. Loss of circulating plasminogen (knockdown) or Plg-RKT prevents caloric restriction-induced satellite cell expansion.\",\n      \"method\": \"MetRSL274G transgenic mouse proteomics to identify liver-secreted plasminogen, plasminogen knockdown, Plg-RKT-/- mice, satellite cell quantification, ERK signaling measurement, human CALERIE trial replication\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and knockdown with defined signaling pathway (Plg-RKT/ERK), replicated in human cohort, but ERK pathway assignment is based on correlation rather than direct in vitro reconstitution\",\n      \"pmids\": [\"38442019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage-specific Plg-RKT deletion protects mice from HFD-induced obesity and MASLD. Mechanistically, mPlg-RKT deficiency reduces hepatic Akt activation, lowers fatty acid synthase expression, activates PPARα fatty acid oxidation, and shifts adipose macrophage polarization from M1 to M2, enhancing insulin sensitivity and reducing plasma free fatty acids available for liver uptake. Hepatocyte-specific Plg-RKT deletion does not confer this protection.\",\n      \"method\": \"Macrophage- and hepatocyte-specific conditional KO mice on HFD, RNA sequencing, Akt and FAS Western blotting, PPARα pathway analysis, adipose macrophage flow cytometry, metabolic phenotyping\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with epistatic comparison (macrophage vs hepatocyte KO), RNA-seq, and multiple mechanistic biochemical readouts\",\n      \"pmids\": [\"41077131\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLGRKT (Plg-RKT) is a structurally unique integral transmembrane plasminogen receptor that exposes a C-terminal lysine on the extracellular face of the cell, tethering plasminogen to the cell surface and promoting its activation to plasmin by both tPA and uPA through physical association with uPAR; this plasmin activity drives macrophage recruitment and migration, macrophage polarization toward M2 phenotype via STAT3 signaling, efferocytosis, fibrinolysis in wounds and on activated platelets, catecholamine release regulation in chromaffin cells, satellite cell proliferation via ERK signaling during caloric restriction, and Lp(a) endocytosis/recycling in hepatocytes, while also regulating mammary lobuloalveolar development and adipose metabolic homeostasis through both plasminogen-dependent and -independent mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLGRKT (Plg-RKT) is an integral membrane plasminogen receptor that functions as a central organizer of cell-surface plasminogen activation, macrophage biology, fibrinolysis, and metabolic homeostasis. It exposes a C-terminal lysine on the extracellular face, directly binding plasminogen in a carboxypeptidase B-sensitive manner, co-localizing and interacting with uPAR and tPA to markedly enhance conversion of plasminogen to plasmin on the surfaces of monocytes/macrophages, platelets, and other cell types [PMID:19897580, PMID:32842150]. In macrophages, PLGRKT is required for plasminogen-dependent chemotactic migration, inflammatory recruitment, M2 polarization via STAT3 signaling, and efferocytosis; macrophage-specific deletion reshapes adipose inflammation and protects against diet-induced obesity and hepatic steatosis by shifting macrophage polarization, suppressing hepatic Akt/FAS lipogenesis, and activating PPARα-dependent fatty acid oxidation [PMID:31316511, PMID:31221672, PMID:41077131]. Beyond the immune compartment, PLGRKT drives mammary lobuloalveolar development through both fibrinolytic and plasminogen-independent mechanisms, mediates hepatic Lp(a) endocytosis and intracellular trafficking, regulates catecholamine secretion in chromaffin cells, promotes satellite cell proliferation via ERK signaling during caloric restriction, and supports fibrin clearance in wound healing [PMID:29495105, PMID:28003220, PMID:21795689, PMID:38442019, PMID:33311441].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"The identity of a transmembrane plasminogen receptor exposing a C-terminal lysine was unknown; proteomic discovery of Plg-RKT established it as a novel integral membrane receptor that co-localizes with uPAR and directly enhances cell-surface plasminogen activation, defining the founding molecular mechanism.\",\n      \"evidence\": \"MudPIT proteomics, carboxypeptidase B-sensitive binding assays, co-localization imaging, and plasminogen activation assays in monocytoid cells\",\n      \"pmids\": [\"19897580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure and topology of the transmembrane domain not resolved\", \"Stoichiometry of Plg-RKT/uPAR complex not determined\", \"Whether Plg-RKT has functions independent of plasminogen binding was unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether Plg-RKT physically associates with uPAR and has functional consequences beyond plasminogen binding was unclear; co-immunoprecipitation confirmed a direct uPAR interaction and functional assays showed Plg-RKT negatively regulates nicotine-evoked catecholamine release through plasmin-mediated prohormone processing, extending its role to neuroendocrine secretion.\",\n      \"evidence\": \"Co-IP with uPAR, GFP-fusion plasma membrane localization, FACS, overexpression plasminogen activation assays, antibody blockade, [³H]norepinephrine secretion in catecholaminergic cells\",\n      \"pmids\": [\"21795689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catecholamine regulation is relevant in vivo not tested\", \"Identity of prohormone substrates cleaved by Plg-RKT-generated plasmin not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The in vivo requirement of Plg-RKT for plasminogen-dependent cell migration and tissue-level physiology was unproven; global knockout mice demonstrated that Plg-RKT is essential for macrophage plasminogen binding and recruitment in peritonitis and for mammary function (lactation failure), establishing it as a non-redundant plasminogen receptor in vivo.\",\n      \"evidence\": \"Homologous recombination KO mice, peritonitis model, plasminogen binding on KO macrophages, lactation phenotype\",\n      \"pmids\": [\"27714956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions (myeloid vs. epithelial) not dissected\", \"Whether lactation failure is plasminogen-dependent or -independent was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether Plg-RKT mediates lipoprotein uptake was unknown; KO and overexpression studies showed it is a receptor for Lp(a) endocytosis in hepatocytes, with apo(a) recycled through Rab5/Rab11 endosomal compartments and LDL degraded in lysosomes, revealing a distinct endocytic trafficking function.\",\n      \"evidence\": \"PlgRKT KO and OE in HAP1 and hepatoma cells, confocal microscopy with Rab5/Rab11 markers, flow cytometry, Western blot\",\n      \"pmids\": [\"28003220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Lp(a) endocytosis requires plasminogen co-binding not tested\", \"Structural basis for Lp(a) recognition not determined\", \"In vivo hepatic Lp(a) clearance in KO mice not reported\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether the lactation defect was purely fibrinolytic was untested; fibrinogen epistasis showed that lobuloalveolar developmental failure involves plasminogen-independent mechanisms (EGF downregulation, Mcl-1 loss, absent epithelial proliferation, stromal fibrosis), demonstrating Plg-RKT has functions beyond fibrin clearance.\",\n      \"evidence\": \"Plg-RKT KO mice, fibrin staining, fibrinogen double-KO epistasis, Ki67/apoptosis assays, transcriptional profiling of mammary gland\",\n      \"pmids\": [\"29495105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target mediating EGF regulation not identified\", \"Whether Plg-RKT signals independently of plasmin generation not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The downstream signaling through which Plg-RKT shapes macrophage phenotype was unknown; KO macrophages revealed that Plg-RKT and plasminogen drive M2 polarization via STAT3 phosphorylation and are required for efferocytosis, linking the receptor to resolution of inflammation.\",\n      \"evidence\": \"Plg-RKT−/− and Plg−/− BMDMs, STAT3 phosphorylation Western blot, flow cytometry for CD206/Arg-1, in vivo/in vitro efferocytosis, murine pleurisy model\",\n      \"pmids\": [\"31316511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How plasmin activates STAT3 (direct vs. indirect receptor signaling) not resolved\", \"Whether efferocytosis defect is purely polarization-dependent or involves separate adhesion mechanism unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Which monocyte subsets depend on Plg-RKT for migration was unresolved; differential expression on proinflammatory CD14++CD16+ (human) and Ly6Chigh (mouse) monocytes and antibody blockade showed Plg-RKT is selectively required for plasmin-dependent directional migration of inflammatory monocyte subsets.\",\n      \"evidence\": \"Flow cytometry of monocyte subsets, anti-Plg-RKT antibody migration blockade, Plg-RKT−/− peritonitis, immunohistochemistry of human atherosclerotic plaques\",\n      \"pmids\": [\"31221672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism regulating differential Plg-RKT surface expression across monocyte subsets not identified\", \"Therapeutic relevance of blocking Plg-RKT in atherosclerosis not tested interventionally\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific roles of Plg-RKT in wound healing were undefined; conditional KO studies showed that myeloid Plg-RKT promotes fibrin clearance and wound repair (loss delays healing), while keratinocyte Plg-RKT paradoxically restrains wound closure (loss accelerates it via filaggrin/caspase-14 upregulation), revealing opposing tissue-specific functions.\",\n      \"evidence\": \"Global and cell-type-specific (myeloid, keratinocyte) KO mice, burn wound model, fibrinogen epistasis, gene expression profiling\",\n      \"pmids\": [\"33311441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How keratinocyte Plg-RKT suppresses filaggrin/caspase-14 mechanistically not resolved\", \"Whether keratinocyte phenotype is plasminogen-dependent not formally tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether Plg-RKT functions on platelets was unknown; Plg-RKT was found in platelet membranes and shown to co-localize with platelet-derived plasminogen upon activation, driving local fibrinolysis in a lysine-dependent manner, establishing platelets as an autonomous fibrinolytic unit via Plg-RKT.\",\n      \"evidence\": \"Western blot of platelet membrane fractions, confocal microscopy, flow cytometry, Plg-RKT−/− and plasminogen−/− platelets, fluorescent clot and turbidimetric fibrinolysis assays, ε-aminocaproic acid competition\",\n      \"pmids\": [\"32842150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of platelet Plg-RKT to in vivo thrombolysis not tested with platelet-specific KO\", \"Whether platelet Plg-RKT influences thrombus stability under flow conditions unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether Plg-RKT regulates systemic metabolism was unexplored; global KO on high-fat diet revealed worsened obesity, insulin resistance, hepatic steatosis, and impaired adipogenesis linked to reduced PPARγ expression, suggesting a metabolic role beyond fibrinolysis.\",\n      \"evidence\": \"Plg-RKT−/− mice on HFD, glucose/insulin tolerance tests, adipose histology, 3T3-L1 and primary preadipocyte cultures, RT-PCR for PPARγ\",\n      \"pmids\": [\"34897983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PPARγ regulation mechanism (direct transcriptional effect vs. indirect via plasmin) not established\", \"Adipogenic phenotype not confirmed with adipocyte-specific conditional KO\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether Plg-RKT transduces inter-organ endocrine signals was unknown; liver-secreted plasminogen was shown to signal through Plg-RKT on satellite cells to promote their proliferation via ERK during caloric restriction, establishing a hepatokine–receptor axis for muscle stem cell regulation.\",\n      \"evidence\": \"MetRSL274G transgenic proteomics, plasminogen knockdown, Plg-RKT−/− mice, satellite cell quantification, ERK measurement, human CALERIE trial replication\",\n      \"pmids\": [\"38442019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct reconstitution of plasminogen/Plg-RKT/ERK signaling in isolated satellite cells not performed\", \"Whether plasmin generation or intact plasminogen binding activates ERK not distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Which cell type mediates Plg-RKT's metabolic protection was unresolved; macrophage-specific but not hepatocyte-specific deletion protected against HFD-induced obesity and MASLD by reducing hepatic Akt/FAS lipogenesis, activating PPARα oxidation, and shifting adipose macrophages toward M2, pinpointing macrophage Plg-RKT as the critical metabolic effector.\",\n      \"evidence\": \"Macrophage- and hepatocyte-specific conditional KO on HFD, RNA-seq, Akt/FAS Western blot, PPARα pathway analysis, adipose macrophage flow cytometry\",\n      \"pmids\": [\"41077131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How macrophage Plg-RKT remotely regulates hepatic Akt remains mechanistically unclear\", \"Whether the metabolic phenotype requires plasminogen not tested via epistasis with Plg KO\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) the structural basis for Plg-RKT's C-terminal lysine exposure and uPAR interaction; (2) whether Plg-RKT transduces intracellular signals independently of plasmin generation; (3) the mechanism by which macrophage Plg-RKT remotely controls hepatic lipogenesis; and (4) whether Plg-RKT represents a viable therapeutic target for metabolic or fibrinolytic disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure available\", \"Plasmin-independent signaling not biochemically reconstituted\", \"Therapeutic targeting not explored in preclinical intervention studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLAUR\",\n      \"PLAT\",\n      \"PLG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}