Affinage

Showing CLEC1B — CLEC-2 is a alias.

CLEC1B

C-type lectin domain family 1 member B · UniProt Q9P126

Length
229 aa
Mass
26.6 kDa
Annotated
2026-06-09
100 papers in source corpus 51 papers cited in narrative 51 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLEC1B (CLEC-2) is a platelet- and megakaryocyte-restricted C-type lectin-like receptor that couples ligand engagement to Syk-dependent tyrosine kinase signaling and serves as the platelet sensor for the mucin-type ligand podoplanin (PMID:16174766, PMID:17616532, PMID:25150298). It was first isolated as the platelet receptor for the snake venom toxin rhodocytin and defined a signaling pathway in which receptor engagement triggers phosphorylation of a single cytoplasmic YXXL (hemITAM) motif, recruitment and activation of Syk, and downstream PLCγ2 activation (PMID:16174766). Because CLEC-2 carries only one YXXL yet must engage a kinase that normally requires tandem ITAMs, the receptor functions as a non-disulfide-linked homodimer, allowing the two SH2 domains of a single Syk to be cross-linked across two phosphorylated monomers in a 2:1 stoichiometry (PMID:19824697, PMID:20154219). Signal initiation requires ligand-induced clustering, translocation to lipid rafts, and—unusually—uses Syk rather than Src family kinases as the primary kinase for hemITAM phosphorylation, with Src kinases acting downstream and with Btk and Gq/GPCR (ADP/TxA2) inputs providing positive feedback (PMID:21098033, PMID:20154214, PMID:25368330, PMID:28705934, PMID:31949019). Crystallographic and mutational work places the ligand-binding site on the non-canonical 'side' face of the C-type lectin domain, where consecutive acidic residues of podoplanin and rhodocytin engage common arginine residues, with podoplanin recognition additionally requiring its sialylated disialyl-core1 O-glycan at Thr52 (PMID:17132623, PMID:17944973, PMID:25458834, PMID:30190281). Beyond podoplanin and rhodocytin, CLEC-2 binds fucoidan, heme, and S100A13 (PMID:23341451, PMID:26418160, PMID:33843987). In vivo, platelet/megakaryocyte CLEC-2–podoplanin signaling is essential for embryonic blood–lymphatic vessel separation, lymph node integrity, cerebrovascular patterning, and hematopoietic stem cell maintenance via megakaryocyte thrombopoietin production (PMID:20363774, PMID:22556408, PMID:24532804, PMID:26552707, PMID:25908104), and it regulates hemostasis and thrombosis, including a hemITAM-independent adhesive contribution to hemostasis (PMID:19641185, PMID:20525685, PMID:28835437). The CLEC-2–podoplanin axis drives deep vein thrombosis, cancer-associated thrombosis, and cerebral venous thrombosis, and modulates inflammation in sepsis, liver injury, and macrophage trafficking, while CLEC-2 on dendritic cells and macrophages controls migration through podoplanin engagement (PMID:22884313, PMID:28104688, PMID:29269852, PMID:32321925, PMID:34163489, PMID:39195988, PMID:37473844).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2005 High

    Established the existence and signaling logic of a novel platelet activation receptor, defining how a single-YXXL C-type lectin transduces a signal through Syk and PLCγ2.

    Evidence Rhodocytin affinity chromatography for receptor identification with Syk/PLCγ2 knockout mouse platelets and Src-family inhibitor

    PMID:16174766

    Open questions at the time
    • Endogenous physiological ligand unknown at this stage
    • Stoichiometry of Syk engagement to a single YXXL unexplained
  2. 2006 High

    Provided the first atomic structure of the CLEC-2 ectodomain, localizing the ligand-binding surface and arguing against large ligand-induced conformational change.

    Evidence X-ray crystallography at 1.6 Å with site-directed mutagenesis and surface plasmon resonance for rhodocytin binding

    PMID:17132623

    Open questions at the time
    • Structure of the endogenous ligand complex not resolved
    • How binding triggers cytoplasmic signaling not addressed
  3. 2007 High

    Identified podoplanin as the endogenous CLEC-2 ligand and defined the glycan and protein determinants of recognition, transforming CLEC-2 from a toxin receptor into a physiological signaling axis.

    Evidence Flow cytometry, recombinant CLEC-2 inhibition and platelet aggregation assays, plus deletion-mutant Fc chimeras and synthetic disialyl-core1 glycopeptides identifying Thr52 O-glycan dependence

    PMID:17616532 PMID:17944973

    Open questions at the time
    • Affinity and direct binding not yet quantified
    • Tissue sources of podoplanin engaging platelets not mapped
  4. 2007 High

    Dissected the cytoplasmic signaling motif, showing both Syk SH2 domains and the upstream DEDG triacidic sequence are required, hinting that receptor dimerization underlies hemITAM function.

    Evidence YXXL and DEDG mutagenesis with Syk SH2-domain mutants and chimeric receptors in cell-line signaling assays

    PMID:17339324

    Open questions at the time
    • Physical demonstration of receptor dimerization still lacking
    • Role of DEDG residues in phosphorylation mechanism unresolved
  5. 2008 High

    Quantified direct CLEC-2–podoplanin binding and the rhodocytin oligomeric state, supporting a clustering model for receptor activation, and identified G6b-B as an inhibitory counter-receptor.

    Evidence SPR affinity measurement (24.5 µM) with DT-40 cell activation, rhodocytin crystallography with docking, and NFAT reporter/ITIM mutant analysis of G6b-B

    PMID:18215137 PMID:18583525 PMID:18955485

    Open questions at the time
    • Clustering mechanism supported only by computational docking
    • G6b-B phosphatase effector remained unidentified (SHP1/2/SHIP-independent)
  6. 2009 High

    Resolved the long-standing single-YXXL paradox by demonstrating CLEC-2 forms a homodimer that allows one Syk to bridge two phosphorylated monomers, and showed CLEC-2 is essential for platelet aggregation and thrombosis.

    Evidence Multiple biophysical methods (BRET, gel filtration, AUC, MALS, SPR) for dimerization, plus antibody depletion in mice with flow-chamber aggregation and in vivo thrombosis assays

    PMID:19641185 PMID:19824697

    Open questions at the time
    • Whether dimers pre-exist or form upon ligand binding not fully resolved here
    • Contribution of CLEC-2 to bleeding versus thrombosis ambiguous across models
  7. 2009 Medium

    Extended CLEC-2 function beyond platelets to neutrophils, where it acts as a Syk-coupled phagocytic and cytokine-inducing receptor, and established Syk as upstream of CLEC-2's own phosphorylation.

    Evidence Primary neutrophil flow cytometry, phagocytosis and cytokine assays, chimeric receptor mutagenesis, plus Syk inhibitor R406 in human platelets

    PMID:19299712 PMID:19422460

    Open questions at the time
    • Neutrophil CLEC-2 expression restricted and context-dependent (single lab)
    • Mechanism by which Syk feeds back to phosphorylate the hemITAM not fully defined
  8. 2010 High

    Defined the proximal biochemistry and biophysics of activation—Syk (not Src) as the hemITAM kinase, lipid-raft translocation, actin/Rac1/secretion dependence, and 2:1 Syk:hemITAM cross-linking—and established CLEC-2's essential developmental role in blood–lymphatic separation.

    Evidence Kinase-specific knockout mouse platelets, raft fractionation and cholesterol depletion, peptide pull-down/SPR/tryptophan fluorescence/EM, and constitutive plus PF4-Cre conditional knockouts with intravital microscopy and genetic epistasis to PDPN/SLP-76

    PMID:20154214 PMID:20154219 PMID:20363774 PMID:20525685 PMID:21098033

    Open questions at the time
    • Precise trigger ordering clustering, raft entry, and phosphorylation incompletely resolved
    • Downstream secreted mediators of lymphatic separation not yet identified
  9. 2011 High

    Showed lineage-restricted CLEC-2/Syk signaling in platelets directly controls lymphatic and cerebrovascular development by acting on endothelial cell migration and adhesion.

    Evidence Megakaryocyte/platelet-lineage conditional Cre-lox knockouts with LEC migration/adhesion assays comparing platelets versus releasate

    PMID:22186994

    Open questions at the time
    • Identity of platelet-borne effector versus contact signal not resolved here
    • Mechanism linking platelet signaling to endothelial behavior unspecified
  10. 2012 High

    Identified secreted mediators (BMP-9) and signaling outputs (RhoA/Rac1, membrane protrusions) downstream of CLEC-2, extending its role to dendritic cell migration and confirming platelet CLEC-2 governs blood/lymphatic vessel separation.

    Evidence Platelet-specific and DC-specific conditional knockouts with LEC tube-formation/migration assays, BMP-9 identification, and RhoA/myosin/Vav/Rac1 readouts with in vivo DC trafficking

    PMID:22556408 PMID:22884313

    Open questions at the time
    • Relative contribution of BMP-9 versus other mediators in vivo unquantified
    • How DC CLEC-2 signaling integrates with platelet CLEC-2 functions unclear
  11. 2013 High

    Established CLEC-2 as a tissue-organizing receptor in lymphoid stroma, releasing S1P to maintain HEV integrity, and confirmed fucoidan as a CLEC-2 agonist.

    Evidence FRC- and platelet-specific conditional knockouts with platelet-infusion rescue and S1P pathway analysis, plus platelet-specific CLEC-2 knockout and FcRγ-null platelets with fucoidan

    PMID:23341451 PMID:23995678

    Open questions at the time
    • Whether S1P acts directly or via additional mediators on HEVs not fully dissected
    • Physiological source of fucoidan-like sulfated ligands in vivo unknown
  12. 2014 High

    Defined the structural basis of dual-ligand recognition on the non-canonical side face, demonstrated ligand-driven membrane clustering, and revealed CLEC-2's roles in lymph node morphogenesis, stromal contractility, and as an activated-platelet marker.

    Evidence CLEC-2–podoplanin and CLEC-2–rhodocytin co-crystal structures, supported-lipid-bilayer FLIM/dSTORM clustering with Src/Syk perturbation, conditional knockouts for lymph node and FRC contractility phenotypes, and antibody-based shedding/copy-number quantitation

    PMID:24532804 PMID:25150298 PMID:25347465 PMID:25368330 PMID:25458834

    Open questions at the time
    • Structural model of the full clustered signaling assembly not solved
    • Mechanism converting clustering to hemITAM phosphorylation at the membrane incomplete
  13. 2015 High

    Placed CLEC-2 at the center of bone marrow niche function—driving megakaryocyte thrombopoietin and CCL5 outputs for HSC maintenance and proplatelet formation—identified additional ligands and signaling branches, and dissected antibody-induced internalization.

    Evidence Megakaryocyte-specific conditional knockouts with Syk/Lcp2/Plcg2 knockdown and Thpo rescue, MK-FRC co-culture with CCL5, S100A13 identification by protein array/SPR, keratinocyte RhoA/E-cadherin assays, 2CP-defined Akt1/PDK1 and PKCµ branches, and Syk-KO/Src-inhibitor internalization studies

    PMID:25795918 PMID:26418160 PMID:26528756 PMID:26552707 PMID:26597882 PMID:26796360

    Open questions at the time
    • Baseline VSMC ligand distinct from S100A13 remains unidentified
    • Physiological relevance of Akt1/PDK1 and PKCµ branches beyond pharmacology unclear
  14. 2017 High

    Separated CLEC-2's signaling-dependent developmental role from a hemITAM-independent adhesive role in hemostasis, defined GPCR/Gq potentiation of proximal signaling, and linked the CLEC-2–podoplanin axis to DVT and to anti-inflammatory control of sepsis.

    Evidence Y7A hemITAM-null knockin mouse with anti-CLEC-2 Fab', Gq-KO/UBO-QIC biochemistry, IVC stenosis DVT model with anti-podoplanin neutralization, and platelet-specific knockouts in two sepsis models

    PMID:28104688 PMID:28705934 PMID:28835437 PMID:29269852

    Open questions at the time
    • Molecular nature of the hemITAM-independent adhesive function undefined
    • Identity of podoplanin-expressing cells driving the sepsis phenotype incompletely mapped
  15. 2018 High

    Established CLEC-2 as an initiator of platelet–leukocyte inflammatory axes (dengue), refined ligand-binding residues amenable to inhibition, defined the rhodocytin oligomeric requirement, and identified CD37 as a membrane organizer of CLEC-2.

    Evidence CLEC-2 blockade with EV characterization and dengue lethality model, SPR/docking/mutagenesis (N120/N210/K211) with cobalt hematoporphyrin, recombinant rhodocytin oligomer mutagenesis with metastasis models, and CD37 co-IP with Cd37-KO myeloid migration assays

    PMID:29488681 PMID:30185523 PMID:30190281 PMID:31160588

    Open questions at the time
    • CD37–CLEC-2 interaction based on single-lab co-IP without structural detail
    • Whether identified inhibitor binding sites overlap the physiological podoplanin interface only partially resolved
  16. 2019 Medium

    Characterized distinct mechanisms of CLEC-2 release—MMP-2-mediated ectodomain shedding and microparticle-associated whole-receptor release—distinguishing it from GPVI shedding biology.

    Evidence Metalloproteinase inhibitor panel with ADAM10-specific inhibitor, microparticle characterization, and ELISA for plasma fragments

    PMID:31165998

    Open questions at the time
    • Single-lab pharmacological inference of MMP-2 involvement
    • Functional consequence of soluble versus microparticle CLEC-2 unestablished
  17. 2020 High

    Defined a CLEC-2 signaling role in restraining reparative inflammation, where platelet CLEC-2 suppresses TNF-α-driven neutrophil recruitment limiting liver recovery.

    Evidence CLEC-2 antibody blockade in APAP and CCl4 liver injury models with TNF-α and neutrophil readouts and human validation

    PMID:32321925

    Open questions at the time
    • Ligand engaging CLEC-2 in the injured liver not defined
    • Direct cellular target of the TNF-α suppression unclear
  18. 2021 High

    Identified Btk-dependent positive feedback unique to human CLEC-2 signaling, a new heme ligand shared with GPVI, and a secretion-independent mechanism by which platelet CLEC-2 controls inflammatory macrophage trafficking.

    Evidence Ibrutinib/acalabrutinib titration with XLA patient platelets and species comparison, SPR hemin binding with CLEC-2/GPVI double-knockout platelets and kidney injury model, and platelet-specific knockout with CLEC-2-Fc rescue and podoplanin/CD44/ERM interaction studies

    PMID:31949019 PMID:33843987 PMID:34163489

    Open questions at the time
    • Mouse-versus-human divergence in Btk feedback mechanistically incompletely explained
    • How CLEC-2 engagement modulates macrophage podoplanin/CD44/ERM at the molecular level not fully resolved
  19. 2022 High

    Placed CLEC-2 as a downstream amplifier of GPIbα–VWF signaling driving αIIbβ3 activation and demonstrated cooperative CLEC-2/GPIIb-IIIa signaling can precipitate acute cerebral venous thrombosis.

    Evidence Platelet-specific knockout with VWF binding and αIIbβ3 activation assays in a TTP model, and INU1-Fab/GPIIb-IIIa intervention with transcranial intravital microscopy in a CVT model

    PMID:35157766 PMID:39195988

    Open questions at the time
    • Molecular link between GPIbα engagement and CLEC-2 activation undefined
    • Whether the CVT-like syndrome reflects physiological CLEC-2 ligand engagement or antibody-specific crosslinking unclear
  20. 2023 Medium

    Implicated CLEC-2 in cancer-associated thrombosis via cancer-associated fibroblast podoplanin and podoplanin-bearing extracellular vesicles activating platelets.

    Evidence CAF and EV characterization, CLEC-2-dependent platelet aggregation, and antibody-induced CLEC-2 depletion in tumor-bearing FeCl3 thrombosis model

    PMID:37473844

    Open questions at the time
    • Single-lab single-study evidence
    • Relative in vivo contribution of CAF-surface versus EV podoplanin unquantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis of CLEC-2's hemITAM-independent adhesive function in hemostasis, and the structure of the full clustered ligand–CLEC-2–Syk signaling assembly at the membrane, remain unresolved.
  • No structure of the clustered receptor–Syk signaling unit
  • Adhesive/physical hemostatic function lacks a defined molecular partner
  • Possible homophilic CLEC-2 interactions in thrombus stabilization not biochemically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-109582 Hemostasis 4 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4
Partners
CD37G6BPDPNSYK

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CLEC-2 was identified as the platelet receptor for snake venom rhodocytin via rhodocytin affinity chromatography. The cytosolic tail contains a single YXXL motif that undergoes tyrosine phosphorylation upon activation by rhodocytin. Signaling is abolished in Syk-deficient and PLCγ2-deficient murine platelets and is inhibited by the Src family kinase inhibitor PP2, defining a novel pathway: CLEC-2 activation → YXXL phosphorylation → Syk binding → downstream tyrosine phosphorylation → PLCγ2 activation. Rhodocytin affinity chromatography, cell-line expression, phosphorylation assays, Syk/PLCγ2/LAT/SLP-76/Vav1/Vav3 knockout mouse platelets, pharmacological inhibition Blood High 16174766
2006 Crystal structure of the extracellular domain of human CLEC-2 was solved to 1.6 Å resolution. A semi-helical loop region and flanking residues dominate the ligand-binding surface. Mutational analysis and surface plasmon resonance binding studies identified key residues for rhodocytin binding. Major ligand-induced conformational change is unlikely given the compact fold, but ligand binding could induce a tilt of a 3-10 helical portion of the long loop region. X-ray crystallography (1.6 Å), site-directed mutagenesis, surface plasmon resonance The Journal of biological chemistry High 17132623
2007 Podoplanin was identified as an endogenous ligand for platelet CLEC-2. Association between CLEC-2 and podoplanin was confirmed by flow cytometry and is dependent on sialic acid on O-glycans of podoplanin. Recombinant CLEC-2 inhibited platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, demonstrating CLEC-2 is the functional receptor responsible for podoplanin-induced platelet aggregation. Flow cytometry, recombinant CLEC-2 inhibition assay, platelet aggregation assay The Journal of biological chemistry High 17616532
2007 CLEC-2 signaling requires its single cytosolic YXXL motif; mutation of either SH2 domain of Syk blocks CLEC-2 signaling despite only a single YXXL motif, indicating dimerization is required. The DEDG amino acid sequence upstream of the YXXL, particularly the glycine directly upstream of the tyrosine, is essential for CLEC-2 signaling. CLEC-2 and Dectin-1 share this novel hemITAM signaling mechanism, distinct from DC-SIGN which signals independently of its YXXL. YXXL mutant cell lines, SH2 domain Syk mutants, chimeric receptor analysis, cell line signaling assay, DEDG sequence mutagenesis The Journal of biological chemistry High 17339324
2007 Deletion mutant analysis of CLEC-2 (expressed as Fc chimeras) identified a podoplanin-recognition domain in CLEC-2. The interaction is dependent on both the disialyl-core1 O-glycan at Thr52 of podoplanin and the stereostructure of the podoplanin protein. A disialyl-core1-attached glycopeptide is specifically recognized by CLEC-2. Anti-podoplanin antibody NZ-1 suppressed both the podoplanin-CLEC-2 interaction and podoplanin-induced pulmonary metastasis in vivo. Deletion mutagenesis with Fc chimeras, glycopeptide synthesis and binding assays, in vivo metastasis model with antibody blockade Cancer science High 17944973
2008 Podoplanin on renal cells (HEK-293T/podocytes) was identified as a direct CLEC-2 ligand. Surface plasmon resonance confirmed direct CLEC-2–podoplanin interaction with an affinity of 24.5 ± 3.7 μM, and this interaction is independent of glycosylation of CLEC-2 itself. Podoplanin on HEK-293T cells mediates both binding to CLEC-2 and activation of CLEC-2-transfected DT-40 B-cells. Surface plasmon resonance, recombinant CLEC-2 binding assay, CLEC-2-transfected DT-40 cell activation assay, podoplanin identification by proteomics The Biochemical journal High 18215137
2008 Crystal structure of rhodocytin at 2.4 Å resolution revealed it is the first snake venom C-type lectin-like protein to assemble as a non-disulfide-linked (αβ)2 tetramer. The concave binding surface of rhodocytin is complementary to the CLEC-2 binding interface. Computational docking suggests the (αβ)2 rhodocytin tetramer induces clustering of CLEC-2 receptors on the platelet surface to trigger signaling. X-ray crystallography (2.4 Å), computational protein-protein docking, electrostatic and hydrophobicity analysis Protein science Medium 18583525
2008 G6b-B, a platelet immunoglobulin receptor with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), inhibits both constitutive and agonist-induced signaling by CLEC-2 and GPVI via Src- and Syk-dependent pathways. This inhibitory activity is independent of SHP1, SHP2, and SHIP phosphatases. NFAT reporter assay in cell lines, ITIM tyrosine mutants, SHP1/SHP2/SHIP inhibitor/knockout experiments, Western blotting The Journal of biological chemistry Medium 18955485
2009 CLEC-2 exists as a non-disulfide-linked homodimer, demonstrated by multiple orthogonal biochemical methods. This dimerization allows each Syk molecule to interact with two YXXL motifs (one from each CLEC-2 monomer), providing a mechanistic explanation for how a single YXXL-containing receptor can activate Syk which normally requires tandem YXXL (ITAM). Bioluminescence resonance energy transfer, co-immunoprecipitation, analytical gel filtration, surface plasmon resonance, multiangle light scattering, analytical ultracentrifugation, Western blotting Biochemistry High 19824697
2009 CLEC-2-deficient platelets displayed normal adhesion under flow but severely defective aggregate formation in vitro and in vivo. CLEC-2 deficiency caused increased bleeding times and profound protection from occlusive arterial thrombus formation, establishing an essential role for CLEC-2 in hemostasis and thrombosis. Anti-CLEC-2 antibody-induced depletion in mice, in vitro flow chamber aggregation assay, in vivo thrombosis models, bleeding time measurement Blood High 19641185
2009 CLEC-2 is expressed on murine peripheral blood neutrophils (but not bone marrow or elicited inflammatory neutrophils), where it functions as a phagocytic activation receptor. Crosslinking of CLEC-2 on neutrophils leads to Syk recruitment and production of pro-inflammatory cytokines (TNF-α) in response to rhodocytin. The tyrosine-based cytoplasmic motif is required for these activities. Notably, CLEC-2 stimulation does not induce the respiratory burst. Antibody staining and flow cytometry, chimeric receptor analysis, phagocytosis assay, cytokine ELISA, Syk co-immunoprecipitation Journal of immunology Medium 19299712
2009 The Syk inhibitor R406 markedly inhibited tyrosine phosphorylation of CLEC-2 itself and downstream Syk phosphorylation following CLEC-2 activation, while Syk phosphorylation downstream of GPVI was unaffected. This revealed a critical role for Syk in mediating phosphorylation of the CLEC-2 hemITAM, suggesting Syk functions both downstream and upstream of CLEC-2 phosphorylation. Platelet aggregometry, immunoprecipitation, Western blotting, pharmacological Syk inhibitor (R406) Journal of thrombosis and haemostasis Medium 19422460
2010 CLEC-2-deficient mice are lethal at embryonic/neonatal stages due to disorganized, blood-filled lymphatic vessels and severe edema. Fetal liver cell transplantation demonstrated that CLEC-2 is involved in thrombus stabilization in vitro and in vivo, possibly through homophilic interactions. Loss of CLEC-2 did not significantly increase bleeding tendency. CLEC-2 knockout mouse generation, fetal liver cell transplantation chimeras, intravital thrombus formation assay, histology The Journal of biological chemistry High 20525685
2010 Platelets regulate lymphatic vascular development by interacting with lymphatic endothelial cells through CLEC-2 binding to podoplanin. Genetic loss of CLEC-2 ablates podoplanin binding by platelets and causes embryonic lymphatic vascular defects identical to those in PDPN- or SLP-76-deficient animals. PF4-Cre-mediated deletion of Slp-76 specifically in platelets is sufficient to cause lymphatic vascular defects, placing CLEC-2→SLP-76 signaling in platelets upstream of blood-lymphatic separation. Conditional (PF4-Cre) and constitutive knockout mice, intravital microscopy of platelet aggregates on lymphatic endothelial cells, genetic epistasis Blood High 20363774
2010 CLEC-2 activates Syk through dimerization: peptide pull-down, surface plasmon resonance, tryptophan fluorescence, and quantitative Western blotting demonstrated that Syk activation by CLEC-2 is mediated by cross-linking of the Syk tandem SH2 domains with two phosphorylated CLEC-2 YXXL motifs in a 2:1 stoichiometry. Cross-linking and electron microscopy confirmed CLEC-2 is present as a dimer in resting platelets and forms larger complexes upon activation. Peptide pull-down, surface plasmon resonance, tryptophan fluorescence, quantitative Western blotting, competition experiments, chemical cross-linking, electron microscopy Blood High 20154219
2010 CLEC-2 phosphorylation (hemITAM) is abolished in the absence of Syk but not in the absence of major platelet Src family kinases (Fyn, Lyn, Src) or CD148, nor is it altered by PP2. PLCγ2 phosphorylation remains dependent on Src family kinases. This established that Syk—not Src—is the primary kinase for CLEC-2 hemITAM phosphorylation, with Src family kinases acting downstream. Syk-knockout, Fyn/Lyn/Src/CD148-knockout mouse platelets, PP2 pharmacological inhibition, Western blotting for CLEC-2 and PLCγ2 phosphorylation The Journal of biological chemistry High 21098033
2010 CLEC-2 translocates to lipid rafts upon ligand engagement, and this translocation is essential for hemITAM phosphorylation and signal initiation (shown by sucrose gradient ultracentrifugation and methyl-β-cyclodextrin treatment). HemITAM phosphorylation (but not translocation) additionally requires actin polymerization, Rac1 activation, and release of ADP and thromboxane A2. Sucrose gradient ultracentrifugation, methyl-β-cyclodextrin cholesterol depletion, actin polymerization inhibitors, Rac1 inhibitors, ADP/TxA2 receptor pharmacology, Western blotting Blood High 20154214
2011 Conditional deletion of CLEC-2 or Syk specifically in the megakaryocyte/platelet lineage causes defects in brain vascular and lymphatic development. Platelets (not platelet releasate) directly modulate migration and intercellular adhesion of lymphatic endothelial cells through a pathway dependent on CLEC-2 and Syk. Conditional (megakaryocyte/platelet lineage) Cre-lox knockout mice, lymphatic endothelial cell migration and adhesion assays with platelets vs. platelet releasate, intravital microscopy Blood High 22186994
2012 Platelet-specific deletion of CLEC-2 causes misconnection of blood/lymphatic vessels. CLEC-2-expressing (but not CLEC-2-deficient) platelets inhibit lymphatic endothelial cell migration, proliferation, and tube formation. Supernatants from activated platelets replicate this inhibition. BMP-9, present in platelets and released upon CLEC-2 activation, specifically inhibits LEC tube formation and plays a key role in blood/lymphatic vessel separation. Platelet-specific CLEC-2 knockout mice, LEC migration/proliferation/tube formation assays, activated platelet supernatant experiments, BMP-9 identification and functional assays The Journal of biological chemistry High 22556408
2012 CLEC-2 engagement of podoplanin on stromal surfaces was necessary and sufficient to induce membrane protrusions in dendritic cells. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation, and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes. DC-specific CLEC-2 conditional knockout mice, RhoA/myosin light-chain phosphorylation assays, Vav/Rac1 inhibitor studies, DC migration assays in lymph nodes, live imaging Immunity High 22884313
2012 The upstream triacidic amino acid (DEDG) sequence in the CLEC-2 cytoplasmic tail is required for signaling through the hemITAM. Surface plasmon resonance and phosphorylation studies demonstrated that the triacidic amino acids are required for YXXL phosphorylation. HemITAM signaling is restricted to Syk (not ZAP-70), shown using Syk-deficient and ZAP-70-deficient cell lines. Site-directed mutagenesis of DEDG sequence, surface plasmon resonance, phosphorylation assays, Syk-deficient and ZAP-70-deficient cell lines The Journal of biological chemistry High 23264619
2013 Podoplanin (PDPN) on fibroblastic reticular cells (FRCs) surrounding high endothelial venules acts as an activating ligand for platelet CLEC-2. CLEC-2 activation induces release of sphingosine-1-phosphate (S1P) from platelets, which promotes VE-cadherin expression on HEVs. Mice lacking FRC podoplanin or platelet CLEC-2 showed reduced VE-cadherin on HEVs; infusion of wild-type platelets restored HEV integrity in CLEC-2-deficient mice. Conditional knockout mice (FRC-specific PDPN, platelet-specific CLEC-2), VE-cadherin measurement, platelet infusion rescue experiment, S1P pathway analysis, ex vivo HEV assay Nature High 23995678
2013 Fucoidan (a sulfated polysaccharide) induces platelet activation through CLEC-2 via a Src family kinase (SFK)- and Syk-dependent pathway. Fucoidan-induced platelet activation was completely abolished in platelet-specific CLEC-2 knockout murine platelets, but only slightly inhibited in FcRγ-chain null mice, establishing CLEC-2 as the primary receptor. Platelet-specific CLEC-2 knockout mice, FcRγ-null mice, SFK/Syk inhibitors, aggregometry, phosphorylation assays The Journal of biological chemistry High 23341451
2014 Crystal structure of CLEC-2 in complex with O-glycosylated podoplanin peptide and with non-glycosylated rhodocytin revealed that both ligands bind to the non-canonical 'side' face of CLEC-2. Common interaction involves consecutive acidic residues on ligands binding to the same arginine residues on CLEC-2. For podoplanin, the sialic acid carboxyl group provides a second binding interaction; for rhodocytin, the C-terminus of the α-subunit interacts differently at this second site. X-ray crystallography of CLEC-2–ligand complexes Structure High 25458834
2014 CLEC-2 expression on platelets is not regulated by proteolytic shedding (unlike GPVI and FcγRIIa, which are cleaved upon CLEC-2 activation). CLEC-2 is restricted to platelets with ~2000 copies per cell. CLEC-2 and GPVI are expressed on CD41+ microparticles in megakaryocyte cultures, but microparticles derived from activated platelets only express CLEC-2, making CLEC-2 a marker for activated platelet-derived microparticles. Monoclonal antibody-based flow cytometry, CLEC-2 copy number quantitation, platelet activation and shedding assays, microparticle characterization Blood Medium 25150298
2014 Podoplanin on FRCs regulates actomyosin contractility in FRCs through CLEC-2. Under resting conditions, podoplanin endows FRCs with contractile function and maintains tension in the reticular network. Upon inflammation, CLEC-2 on mature DCs potently attenuates podoplanin-mediated contractility in FRCs, resulting in FRC relaxation and reduced tissue stiffness. Collagen gel contraction assay, myosin light chain phosphorylation assays, conditional knockout mice, 3D tissue imaging, DC-FRC co-culture Nature immunology High 25347465
2014 Syk and Src family kinases in platelets promote clustering of CLEC-2 and its ligand podoplanin on supported lipid bilayers containing mobile podoplanin. CLEC-2-bound podoplanin clusters migrate to the center of the platelet, forming a single structure. Fluorescence lifetime imaging demonstrated molecules within these clusters are within 10 nm. Clusters are disrupted by Src/Syk inhibition. Supported lipid bilayer system with mobile podoplanin, fluorescence lifetime imaging microscopy (FLIM), direct stochastic optical reconstruction microscopy (dSTORM), Src/Syk inhibitors, Syk-deficient mouse platelets The Journal of biological chemistry High 25368330
2014 CLEC-2 deficiency results in absence of lymph nodes at birth due to defective lymphatic endothelial cell proliferation. Platelet-specific CLEC-2 deficiency (PF4-Cre) leads to blood-filled lymph nodes and fibrosis (without a proliferative defect), indicating CLEC-2 expression in platelets specifically is required for lymph node integrity. This phenotype is independent of the lymphatic endothelial proliferation defect seen with constitutive CLEC-2 deletion. Constitutive and PF4-Cre conditional CLEC-2 knockout mice, bone marrow chimeras, lymph node histology, LEC proliferation assays, immune response assays Blood High 24532804
2015 CLEC-2 in megakaryocytes mediates production of thrombopoietin (Thpo) and other factors required for HSC maintenance. Megakaryocyte-specific CLEC-2 knockout mice produced lower levels of Thpo and showed reduced HSC quiescence and repopulation potential with extramedullary hematopoiesis. Knockdown of downstream CLEC-2 signaling molecules (Syk, Lcp2, Plcg2) in megakaryocytes decreased Thpo expression. Administration of recombinant Thpo restored stem cell potential. Megakaryocyte-specific CLEC-2 conditional knockout mice, Syk/Lcp2/Plcg2 siRNA knockdown in megakaryocytes, Thpo measurement, HSC quiescence and transplantation assays, recombinant Thpo rescue The Journal of experimental medicine High 26552707
2015 Podoplanin-positive periarteriolar BM fibroblastic reticular cell (FRC)-like cells promote megakaryocyte growth and proplatelet formation through CLEC-2/podoplanin interaction. Megakaryocyte-specific CLEC-2 conditional knockout mice showed decreased immature megakaryocytes. The CLEC-2/podoplanin interaction induces BM FRC-like cells to secrete CCL5, which facilitates proplatelet formation. Megakaryocyte-specific CLEC-2 conditional knockout mice, megakaryocyte-FRC co-culture, recombinant podoplanin stimulation, CCL5 secretion measurement, immunofluorescence of BM sections Blood High 26796360
2015 Podoplanin/CLEC-2 signaling regulates keratinocyte migration via modulating E-cadherin expression through RhoA signaling. Down-regulation of podoplanin in keratinocytes inhibited their migration and was correlated with upregulation of E-cadherin. Both platelets and recombinant CLEC-2 inhibited keratinocyte migration, with downregulation of RhoA activity and upregulation of E-cadherin. Podoplanin siRNA knockdown in NHEKs, platelet/CLEC-2 co-culture migration assays, wound healing assay, RhoA activity measurement, E-cadherin Western blotting The American journal of pathology Medium 26597882
2015 Vascular smooth muscle cells (VSMCs) stimulate platelets and facilitate thrombus formation through platelet CLEC-2. Protein arrays and Biacore analysis identified S100A13 as a CLEC-2 ligand in VSMCs. S100A13 is released upon oxidative stress and immobilized (but not suspended) S100A13 significantly increases thrombus formation on collagen-coated surfaces. However, surface S100A13 on normal VSMCs does not activate platelets, indicating another CLEC-2 ligand mediates baseline VSMC–platelet interaction. Recombinant CLEC-2 binding assays, flow cytometry, immunocytochemistry, thrombus formation assay under flow, FeCl3 animal thrombosis model, protein array, surface plasmon resonance (Biacore) PloS one Medium 26418160
2015 CLEC-2 is internalized from the platelet surface upon anti-CLEC-2 antibody (INU1) treatment through a Src-family kinase-dependent mechanism, followed by intracellular degradation. This internalization is independent of Syk. Syk-deficient mice showed preserved CLEC-2 internalization but largely prevented antibody-induced thrombocytopenia, mechanistically uncoupling CLEC-2 downregulation from thrombocytopenia. Platelet-specific Syk knockout mice, Src family kinase inhibitors, flow cytometry for CLEC-2 surface expression, in vitro and in vivo INU1 treatment Blood High 25795918
2015 Podoplanin on pericytes/neuro-epithelium interacts with CLEC-2 on platelets to guide cerebrovascular patterning and integrity during development. Cerebral vessels were tortuous and aberrantly patterned at E10.5 in podoplanin- and CLEC-2-deficient mice; defective pericyte recruitment and endothelial-pericyte misconnections were observed. Platelet α-granule and dense granule secretion is required, as embryos deficient in platelet GPIIb or granule secretion also developed cerebral hemorrhaging. Conditional and constitutive CLEC-2/podoplanin knockout mice, nestin-Cre podoplanin deletion, 3D light-sheet microscopy, immunofluorescence, electron microscopy Blood High 25908104
2017 Platelet-specific deficiency of CLEC-2 protects mice against deep vein thrombosis (DVT) in an IVC stenosis model. Podoplanin is expressed in the IVC wall near the abluminal endothelium and is upregulated after 48h stenosis in mice that develop thrombi. Inhibition of podoplanin with a neutralizing antibody reduced thrombus size, establishing the CLEC-2–podoplanin axis as a mechanistic driver of DVT. Inducible CLEC-2 knockout and platelet-specific CLEC-2 knockout mice, IVC stenosis model, platelet transfusion rescue, anti-podoplanin neutralizing antibody, immunofluorescence of podoplanin localization Blood High 28104688
2017 Platelet-specific deletion of CLEC-2 (but not GPVI) leads to enhanced systemic inflammation and accelerated organ injury in two mouse models of sepsis. CLEC-2 deficiency is associated with reduced numbers of podoplanin-expressing macrophages despite increased cytokines. Pharmacological inhibition of CLEC-2–podoplanin interaction regulates immune cell infiltration, identifying the podoplanin–CLEC-2 axis as an anti-inflammatory pathway in sepsis. Platelet-specific CLEC-2 and GPVI conditional knockout mice, LPS i.p. and cecal ligation and puncture sepsis models, cytokine measurement, immune cell counting, pharmacological CLEC-2–podoplanin inhibition Nature communications High 29269852
2017 Gq signaling (via PLCβ-PKCα pathway, possibly regulating Src family kinases) potentiates the most proximal event in CLEC-2 signaling—the CLEC-2 receptor tyrosine phosphorylation itself—in response to TxA2 and other GPCR agonists. Using the Gq inhibitor UBO-QIC and Gq-knockout murine platelets, Gq signaling was demonstrated to be essential for GPCR-mediated potentiation of Syk phosphorylation downstream of CLEC-2. Gq-specific inhibitor (UBO-QIC), Gq-knockout mouse platelets, P2Y12/PAR/TP receptor agonists, Western blotting for CLEC-2 and Syk phosphorylation The Journal of biological chemistry High 28705934
2017 CLEC-2 contributes to hemostasis through a mechanism independent of classical hemITAM signaling. A knockin mouse expressing hemITAM-null CLEC-2 (Y7A KI) phenocopied blood-lymphatic mixing/lethality of CLEC-2 KO but not the hemostatic/thrombotic defect. Treatment of Y7A KI mice with function-blocking anti-CLEC-2 Fab' resulted in a thrombus formation defect, revealing a hemITAM signaling-independent (physical/adhesive) role for CLEC-2 in hemostasis. CLEC-2 Y7A hemITAM knockin mouse model, anti-CLEC-2 Fab' treatment, thrombosis assays in vitro and in vivo Blood High 28835437
2018 Dengue virus activates platelets via CLEC-2 to release extracellular vesicles (exosomes and microvesicles). These EVs further activate CLEC5A and TLR2 on neutrophils and macrophages, inducing NET formation and pro-inflammatory cytokine release. Simultaneous blockade of CLEC5A and TLR2 (not CLEC-2) increased survival from DV infection from 30% to 90%, establishing CLEC-2 as the upstream initiator of this platelet-leukocyte inflammatory axis. CLEC-2 functional blocking, EV isolation and characterization, CLEC5A/TLR2 blockade, NET formation assay, cytokine measurement, mouse dengue lethality model Nature communications High 31160588
2018 Surface plasmon resonance and molecular docking identified novel podoplanin-binding sites on CLEC-2: N120, N210, and K211. Cobalt hematoporphyrin (Co-HP) binds directly to CLEC-2 at these sites and inhibits CLEC-2–podoplanin interaction. These binding sites were confirmed by CLEC-2 mutants with alterations in N120 and/or K211. Surface plasmon resonance, molecular docking, CLEC-2 site-directed mutagenesis, platelet aggregation assay, in vivo metastasis and thrombosis models Blood advances High 30190281
2018 Recombinant rhodocytin forms a heterooctamer (four α- and β-subunits). Asp4 in the α-subunit of rhodocytin is required for CLEC-2 binding. An inhibitory mutant rhodocytin (αWTβK53A/R56A) forms a heterotetramer, binds CLEC-2 without inducing platelet aggregation, and blocks CLEC-2–podoplanin interaction-dependent platelet aggregation and experimental lung metastasis. Recombinant rhodocytin expression, mutagenesis, blue native PAGE for multimer analysis, flow cytometry for CLEC-2 binding, platelet aggregometry, in vivo lung metastasis model Journal of thrombosis and haemostasis High 29488681
2018 Tetraspanin CD37 specifically interacts with CLEC-2 and controls CLEC-2 membrane organization. CD37-deficient myeloid cells expressed reduced surface CLEC-2 and showed impaired CLEC-2-dependent adhesion, migration velocity, and actin protrusion formation. CD37 is required for CLEC-2 recruitment in the membrane to podoplanin, and CD37-deficient DCs fail to inhibit actomyosin contractility in lymph node stromal cells. Co-immunoprecipitation of CD37-CLEC-2, Cd37-knockout mice, DC migration and adhesion assays, microcontact printing for CLEC-2 membrane recruitment, actin protrusion assay in 3D collagen Journal of cell science Medium 30185523
2019 Akt1/PDK1 and PKCμ are two alternative CLEC-2 signaling pathways mediating podoplanin-induced platelet activation, identified through analysis of the molecular action of compound 2CP (a direct CLEC-2 binding inhibitor that competes with podoplanin for the same CLEC-2 binding pocket). Compound 2CP binding assay, Akt1/PDK1 and PKCμ pathway analysis, CLEC-2 competitive binding assay, platelet aggregation, in vivo metastasis model Oncotarget Medium 26528756
2019 Soluble CLEC-2 (sCLEC-2) is shed as a fragment partially generated by MMP-2 (not ADAM10/17, which mediate GPVI shedding). Additionally, CLEC-2 is released as a whole molecule associated with platelet microparticles (MP-CLEC-2). This contrasts with sGPVI which is exclusively shed by ADAM10/17. The two proteins are thus released by distinct mechanisms. Metalloproteinase inhibitors/stimulators, ADAM10-specific inhibitor, domain-specific GPVI antibodies, microparticle characterization, ELISA for plasma levels International journal of hematology Medium 31165998
2020 Platelet CLEC-2 signaling blocks reparative neutrophil recruitment in acetaminophen-induced acute liver failure by suppressing TNF-α production. Blocking CLEC-2 signaling enhanced liver recovery from APAP and CCl4 acute toxic liver injuries by increasing TNF-α, which drives reparative hepatic neutrophil recruitment. CLEC-2 signaling blockade (antibody), APAP and CCl4 mouse models, TNF-α measurement, neutrophil enumeration, human and mouse hepatic inflammatory response studies Nature communications High 32321925
2021 Platelet CLEC-2 reduces tissue inflammation by regulating inflammatory macrophage activation and trafficking. The immune regulatory function depends on podoplanin expression on inflammatory macrophages and is independent of platelet activation/secretion. Mechanistically, platelet CLEC-2 and recombinant CLEC-2-Fc accelerate actin rearrangement and macrophage migration by increasing podoplanin and CD44 expression and their interaction with ERM proteins, promoting macrophage emigration to mesenteric lymph nodes. Platelet-specific CLEC-2 knockout mice, LPS peritonitis model, recombinant CLEC-2-Fc treatment, actin rearrangement assay, podoplanin/CD44/ERM protein interaction studies, cytokine measurement, in vivo macrophage tracking Frontiers in immunology High 34163489
2021 Low concentrations of the Btk inhibitor ibrutinib selectively block CLEC-2-mediated activation and tyrosine phosphorylation (including Syk and PLCγ2) in human platelets, while GPVI response is only delayed. Platelets from patients with X-linked agammaglobulinemia (XLA, Btk-deficient) phenocopy this selective CLEC-2 block. The differential effect is explained by a positive feedback role of Btk in CLEC-2 signaling, involving ADP/TxA2-mediated P2Y12/TP receptor co-activation, which is not present in mouse platelets. Ibrutinib and acalabrutinib at titrated concentrations, XLA patient platelets, human and mouse platelet aggregometry, Syk/PLCγ2 phosphorylation, in vivo mouse thrombosis model Haematologica High 31949019
2021 Hemin (heme) directly binds to both CLEC-2 and GPVI on platelets, as demonstrated by Western blotting and surface plasmon resonance. Hemin activates human platelets by stimulating phosphorylation of SYK and PLCγ2 through both receptors. Hemin-induced murine platelet aggregation is almost completely inhibited only in CLEC-2-depleted FcRγ-deficient (GPVI-deficient) double-knockout platelets, and CLEC-2/GPVI signaling contributes to MET formation and rhabdomyolysis-induced acute kidney injury. Surface plasmon resonance for direct hemin-CLEC-2/GPVI binding, CLEC-2 depletion and FcRγ-null mouse platelets, RAKI mouse model, in vitro MET formation assay, Western blotting for SYK/PLCγ2 phosphorylation Blood advances High 33843987
2022 Deletion of platelet CLEC-2 does not prevent VWF binding to platelets via GPIbα but specifically inhibited platelet aggregation and αIIbβ3 activation induced by VWF binding to GPIbα. In a mouse TTP model, CLEC-2 deletion decreased pulmonary arterial thrombosis and severity of thrombocytopenia, establishing CLEC-2 as a downstream mediator of GPIbα-initiated integrin αIIbβ3 activation. Platelet-specific CLEC-2 knockout mice, VWF-platelet binding assay, αIIbβ3 activation measurement, mouse TTP model (anti-ADAMTS13 antibody + VWF infusion), aspirin/eptifibatide treatment Blood High 35157766
2022 Cooperative signaling between CLEC-2 (activated by anti-CLEC-2 Fab INU1) and GPIIb/IIIa triggers a cerebral venous (sinus) thrombosis (CVT)-like syndrome in mice within minutes, characterized by tonic-myoclonic seizures, platelet consumption, and death. Interfering with CLEC-2 signaling or GPIIb/IIIa completely blocked platelet activation and CVT. Blocking GPIIb/IIIa after onset of neurological symptoms protected mice, while heparin did not. INU1-Fab anti-CLEC-2 antibody in mice, GPIIb/IIIa inhibitor, transcranial intravital microscopy of superior sagittal sinus, brain autopsy/histology, seizure monitoring Nature cardiovascular research High 39195988
2023 Cancer-associated fibroblasts (CAFs) co-express podoplanin and induce CLEC-2-dependent platelet aggregation. CAF-derived extracellular vesicles (EVs) also contain podoplanin and activate platelets in a CLEC-2-dependent manner. In tumor-bearing mice, antibody-induced CLEC-2 depletion suppressed venous thrombosis in the tumor-bearing state, establishing CAF-derived podoplanin/EVs as drivers of cancer-associated thrombosis through CLEC-2. CAF characterization by immunofluorescence, podoplanin EV isolation and immunoblotting, platelet aggregation flow cytometry, venous thrombosis model (FeCl3), CLEC-2 depletion antibody (2A2B10) Journal of thrombosis and haemostasis Medium 37473844

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. The Journal of biological chemistry 401 17616532
2005 A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 396 16174766
2010 Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 332 20363774
2013 Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 259 23995678
2019 Functional significance of the platelet immune receptors GPVI and CLEC-2. The Journal of clinical investigation 251 30601137
2012 Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 237 22884313
2007 Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2. Cancer science 230 17944973
2014 The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nature immunology 222 25347465
2006 DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. Journal of virology 205 16940507
2010 Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. The Journal of biological chemistry 202 20525685
2019 Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nature communications 193 31160588
2009 CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 176 19641185
2007 The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade. The Journal of biological chemistry 171 17339324
2013 Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2. PloS one 166 23991201
2019 Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin. Blood 156 31778548
2010 GPVI and CLEC-2 in hemostasis and vascular integrity. Journal of thrombosis and haemostasis : JTH 150 20345705
2017 Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood 146 28104688
2015 Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets. The Journal of clinical investigation 135 26571395
2012 Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells. The Journal of biological chemistry 130 22556408
2017 The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. Nature communications 122 29269852
2010 CLEC-2 activates Syk through dimerization. Blood 116 20154219
2011 CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 113 22186994
2015 CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. The Journal of experimental medicine 109 26552707
2014 CLEC-2 expression is maintained on activated platelets and on platelet microparticles. Blood 103 25150298
2011 Novel platelet activation receptor CLEC-2: from discovery to prospects. Journal of thrombosis and haemostasis : JTH 100 21781241
2009 CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils. Journal of immunology (Baltimore, Md. : 1950) 97 19299712
2014 A platform of C-type lectin-like receptor CLEC-2 for binding O-glycosylated podoplanin and nonglycosylated rhodocytin. Structure (London, England : 1993) 95 25458834
2012 Platelet CLEC-2 and podoplanin in cancer metastasis. Thrombosis research 93 22682130
2009 The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC-2 signaling in platelets. Journal of thrombosis and haemostasis : JTH 91 19422460
2010 Syk-dependent phosphorylation of CLEC-2: a novel mechanism of hem-immunoreceptor tyrosine-based activation motif signaling. The Journal of biological chemistry 88 21098033
2008 Renal cells activate the platelet receptor CLEC-2 through podoplanin. The Biochemical journal 87 18215137
2015 Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis. Oncotarget 84 26528756
2015 Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development. Blood 80 25908104
2020 The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure. Nature communications 72 32321925
2011 CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses. European journal of immunology 72 21728173
2013 The physiological and pathophysiological roles of platelet CLEC-2. Thrombosis and haemostasis 66 23572154
2019 CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections. Frontiers in immunology 63 31867016
2008 Characterization of anti-podoplanin monoclonal antibodies: critical epitopes for neutralizing the interaction between podoplanin and CLEC-2. Hybridoma (2005) 63 18707544
2014 CLEC-2 is required for development and maintenance of lymph nodes. Blood 62 24532804
2014 Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells. The Journal of biological chemistry 60 25368330
2010 Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac. Blood 60 20154214
2013 Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2). The Journal of biological chemistry 57 23341451
2017 Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse. American journal of physiology. Lung cellular and molecular physiology 56 28839100
2018 Cobalt hematoporphyrin inhibits CLEC-2-podoplanin interaction, tumor metastasis, and arterial/venous thrombosis in mice. Blood advances 54 30190281
2016 Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2. Blood 54 26796360
2013 Platelet receptors activated via mulitmerization: glycoprotein VI, GPIb-IX-V, and CLEC-2. Journal of thrombosis and haemostasis : JTH 54 23809136
2006 The crystal structure and mutational binding analysis of the extracellular domain of the platelet-activating receptor CLEC-2. The Journal of biological chemistry 53 17132623
2021 The Role of CLEC-2 and Its Ligands in Thromboinflammation. Frontiers in immunology 51 34177942
2011 Essential in vivo roles of the platelet activation receptor CLEC-2 in tumour metastasis, lymphangiogenesis and thrombus formation. Journal of biochemistry 51 21693546
2021 Low-dose Btk inhibitors selectively block platelet activation by CLEC-2. Haematologica 50 31949019
2009 The platelet receptor CLEC-2 is active as a dimer. Biochemistry 50 19824697
2018 Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction. Blood 49 29853539
2014 Complexity and Diversity of the NKR-P1:Clr (Klrb1:Clec2) Recognition Systems. Frontiers in immunology 49 24917862
2008 G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2. The Journal of biological chemistry 47 18955485
2021 Heme activates platelets and exacerbates rhabdomyolysis-induced acute kidney injury via CLEC-2 and GPVI/FcRγ. Blood advances 43 33843987
2021 Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment. Frontiers in immunology 42 34987523
2015 Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis. PloS one 42 26418160
2018 Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2/podoplanin-dependent platelet aggregation and lung metastasis. Journal of thrombosis and haemostasis : JTH 41 29488681
2017 Platelet CLEC-2: Roles Beyond Hemostasis. Seminars in thrombosis and hemostasis 41 28992650
2015 PDGF upregulates CLEC-2 to induce T regulatory cells. Oncotarget 41 26416420
2020 Novel antiplatelet strategies targeting GPVI, CLEC-2 and tyrosine kinases. Platelets 40 33307909
2008 Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2. Protein science : a publication of the Protein Society 39 18583525
2018 CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage. Translational oncology 38 29525632
2017 CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 38 28835437
2018 Roles of the CLEC-2-podoplanin interaction in tumor progression. Platelets 37 29863945
2018 Significant Hypo-Responsiveness to GPVI and CLEC-2 Agonists in Pre-Term and Full-Term Neonatal Platelets and following Immune Thrombocytopenia. Thrombosis and haemostasis 36 29695020
2015 Activation of glycoprotein VI (GPVI) and C-type lectin-like receptor-2 (CLEC-2) underlies platelet activation by diesel exhaust particles and other charged/hydrophobic ligands. The Biochemical journal 35 25849538
2009 Novel interactions in platelet biology: CLEC-2/podoplanin and laminin/GPVI. Journal of thrombosis and haemostasis : JTH 34 19630798
2015 The expression of mouse CLEC-2 on leucocyte subsets varies according to their anatomical location and inflammatory state. European journal of immunology 33 26173808
2010 A novel mechanism of cytokine release in phagocytes induced by aggretin, a snake venom C-type lectin protein, through CLEC-2 ligation. Journal of thrombosis and haemostasis : JTH 33 20738764
2015 Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization. Blood 32 25795918
2019 Cordycepin suppresses cell proliferation and migration by targeting CLEC2 in human gastric cancer cells via Akt signaling pathway. Life sciences 31 30878262
2019 Soluble CLEC-2 is generated independently of ADAM10 and is increased in plasma in acute coronary syndrome: comparison with soluble GPVI. International journal of hematology 31 31165998
2015 Platelets Regulate the Migration of Keratinocytes via Podoplanin/CLEC-2 Signaling during Cutaneous Wound Healing in Mice. The American journal of pathology 28 26597882
2014 CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo. Blood 28 25085348
2008 Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2. Journal of thrombosis and haemostasis : JTH 28 18826392
2012 Critical Role for an acidic amino acid region in platelet signaling by the HemITAM (hemi-immunoreceptor tyrosine-based activation motif) containing receptor CLEC-2 (C-type lectin receptor-2). The Journal of biological chemistry 27 23264619
2021 The structure of CLEC-2: mechanisms of dimerization and higher-order clustering. Platelets 24 33819136
2012 A detailed proteomic analysis of rhodocytin-activated platelets reveals novel clues on the CLEC-2 signalosome: implications for CLEC-2 signaling regulation. Blood 24 23053573
2010 Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2. Retrovirology 23 20482880
2023 Cancer-associated fibroblasts promote venous thrombosis through podoplanin/CLEC-2 interaction in podoplanin-negative lung cancer mouse model. Journal of thrombosis and haemostasis : JTH 22 37473844
2020 A Comprehensive Tyrosine Phosphoproteomic Analysis Reveals Novel Components of the Platelet CLEC-2 Signaling Cascade. Thrombosis and haemostasis 22 31901221
2011 The novel platelet activation receptor CLEC-2. Platelets 22 21714702
2022 Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation. Nature cardiovascular research 21 39195988
2020 A Role of the Podoplanin-CLEC-2 Axis in Promoting Inflammatory Response After Ischemic Stroke in Mice. Neurotoxicity research 21 33165736
2018 C-type lectin-like receptor 2 (CLEC-2)-dependent dendritic cell migration is controlled by tetraspanin CD37. Journal of cell science 21 30185523
2017 Gq pathway regulates proximal C-type lectin-like receptor-2 (CLEC-2) signaling in platelets. The Journal of biological chemistry 21 28705934
2015 Platelet adhesion to podoplanin under flow is mediated by the receptor CLEC-2 and stabilised by Src/Syk-dependent platelet signalling. Thrombosis and haemostasis 21 25694214
2022 Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP. Blood 20 35157766
2019 Elevated plasma levels of soluble C-type lectin-like receptor 2 (CLEC2) in patients with thrombotic microangiopathy. Thrombosis research 20 30978634
2021 CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis. Frontiers in immunology 19 34163489
2011 Identification of a chicken CLEC-2 homologue, an activating C-type lectin expressed by thrombocytes. Immunogenetics 19 22205394
2005 Crystallization and X-ray diffraction analysis of human CLEC-2. Acta crystallographica. Section F, Structural biology and crystallization communications 19 16511244
2019 Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin. Hematology. American Society of Hematology. Education Program 18 31808911
2014 Human podoplanin-positive monocytes and platelets enhance lymphangiogenesis through the activation of the podoplanin/CLEC-2 axis. Molecular therapy : the journal of the American Society of Gene Therapy 18 24736277
2022 CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear. Thrombosis and haemostasis 17 35817083
2020 Lymphatic blood filling in CLEC-2-deficient mouse models. Platelets 17 32129691
2020 Fucoidan suppresses the gastric cancer cell malignant phenotype and production of TGF-β1 via CLEC-2. Glycobiology 16 31742327
2020 Control of Platelet CLEC-2-Mediated Activation by Receptor Clustering and Tyrosine Kinase Signaling. Biophysical journal 16 32396849
2008 Thrombomodulation via CLEC-2 targeting. Current opinion in pharmacology 16 19091630

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