PLGRKT

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).

1. 2009 High

   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

   PMID:19897580

   Open questions at the time

   • 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
2. 2011 High

   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

   PMID:21795689

   Open questions at the time

   • Whether catecholamine regulation is relevant in vivo not tested
   • Identity of prohormone substrates cleaved by Plg-RKT-generated plasmin not defined
3. 2016 High

   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

   PMID:27714956

   Open questions at the time

   • Cell-type-specific contributions (myeloid vs. epithelial) not dissected
   • Whether lactation failure is plasminogen-dependent or -independent was unknown
4. 2016 High

   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

   PMID:28003220

   Open questions at the time

   • 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
5. 2018 High

   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

   PMID:29495105

   Open questions at the time

   • Direct molecular target mediating EGF regulation not identified
   • Whether Plg-RKT signals independently of plasmin generation not biochemically demonstrated
6. 2019 High

   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

   PMID:31316511

   Open questions at the time

   • How plasmin activates STAT3 (direct vs. indirect receptor signaling) not resolved
   • Whether efferocytosis defect is purely polarization-dependent or involves separate adhesion mechanism unknown
7. 2019 High

   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

   PMID:31221672

   Open questions at the time

   • Mechanism regulating differential Plg-RKT surface expression across monocyte subsets not identified
   • Therapeutic relevance of blocking Plg-RKT in atherosclerosis not tested interventionally
8. 2020 High

   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

   PMID:33311441

   Open questions at the time

   • How keratinocyte Plg-RKT suppresses filaggrin/caspase-14 mechanistically not resolved
   • Whether keratinocyte phenotype is plasminogen-dependent not formally tested
9. 2021 High

   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

   PMID:32842150

   Open questions at the time

   • 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
10. 2021 Medium

    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

    PMID:34897983

    Open questions at the time

    • PPARγ regulation mechanism (direct transcriptional effect vs. indirect via plasmin) not established
    • Adipogenic phenotype not confirmed with adipocyte-specific conditional KO
11. 2024 Medium

    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

    PMID:38442019

    Open questions at the time

    • 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
12. 2025 High

    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

    PMID:41077131

    Open questions at the time

    • How macrophage Plg-RKT remotely regulates hepatic Akt remains mechanistically unclear
    • Whether the metabolic phenotype requires plasminogen not tested via epistasis with Plg KO

• 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.
• No high-resolution structure available
• Plasmin-independent signaling not biochemically reconstituted
• Therapeutic targeting not explored in preclinical intervention studies