Affinage

CLEC1B

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

Length
229 aa
Mass
26.6 kDa
Annotated
2026-04-28
100 papers in source corpus 51 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLEC-2 (CLEC1B) is a C-type lectin-like receptor expressed on platelets, megakaryocytes, dendritic cells, and neutrophils that functions as a hemITAM-coupled pattern recognition receptor linking innate immune sensing to hemostasis, vascular development, and inflammation. Its primary endogenous ligand podoplanin and exogenous agonists (rhodocytin, fucoidan, hemin, S100A13) bind a non-canonical 'side' face of the extracellular domain, inducing receptor dimerization and higher-order clustering that enables Syk recruitment in a 2:1 stoichiometry via tandem SH2 domains bridging two phosphorylated hemITAM YXXL motifs; hemITAM phosphorylation itself requires lipid raft translocation, actin polymerization, and positive feedback through ADP/TxA2/Gq/PLCβ/PKCα/Src pathways, driving a Syk→SLP-76→PLCγ2→Ca²⁺ cascade that triggers platelet aggregation, granule secretion (releasing S1P, TGF-β, BMP-9, CCL5), and extracellular vesicle release (PMID:16174766, PMID:25458834, PMID:20154219, PMID:20154214, PMID:28705934, PMID:31160588). Genetically, platelet CLEC-2/podoplanin signaling is essential for embryonic blood–lymphatic vessel separation, lymph node development and maintenance, cerebrovascular patterning, lung alveolar duct formation, HEV vascular integrity, and megakaryopoiesis, and contributes pathologically to arterial and venous thrombosis, infection-driven thromboinflammation, tumor metastasis, and regulation of macrophage-mediated inflammation (PMID:20525685, PMID:20363774, PMID:25908104, PMID:29853539, PMID:23995678, PMID:24532804, PMID:26552707, PMID:28104688, PMID:26571395, PMID:34163489).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Identifying CLEC-2 as the platelet receptor for rhodocytin established that a single hemITAM YXXL motif could activate a Syk→PLCγ2 signaling cascade, defining a new receptor class distinct from classical dual-ITAM receptors.

    Evidence Rhodocytin affinity chromatography, Syk−/− and PLCγ2−/− mouse platelets, kinase inhibitors

    PMID:16174766

    Open questions at the time
    • Endogenous ligand unknown
    • Mechanism by which single YXXL engages tandem SH2 domains of Syk unresolved
    • In vivo physiological role not established
  2. 2006 High

    The 1.6 Å crystal structure of CLEC-2 revealed the ligand-binding surface centered on a semi-helical loop, providing the first structural framework for understanding receptor–ligand specificity.

    Evidence X-ray crystallography, site-directed mutagenesis, SPR

    PMID:17132623

    Open questions at the time
    • No co-crystal with ligand yet
    • Dimerization interface not resolved
  3. 2007 High

    Identification of podoplanin as the endogenous CLEC-2 ligand answered what physiological signal activates this receptor and revealed dependence on sialylated O-glycans, while parallel signaling studies showed the DEDG acidic motif upstream of YXXL is critical for hemITAM function.

    Evidence Flow cytometry binding, recombinant protein inhibition, glycopeptide mapping, mutagenesis in mutant cell lines

    PMID:17339324 PMID:17616532 PMID:17944973

    Open questions at the time
    • Affinity of CLEC-2/podoplanin interaction not quantified
    • Structural basis of glycan recognition unknown
    • In vivo developmental role not yet demonstrated
  4. 2009 High

    Demonstration that CLEC-2 exists as a pre-formed homodimer resolved how a single hemITAM receptor engages Syk's tandem SH2 domains — each SH2 domain binds one phospho-YXXL from a different monomer — and antibody-mediated CLEC-2 depletion established its requirement for thrombus stability in vivo.

    Evidence BRET, co-IP, analytical ultracentrifugation, MALS, intravital microscopy, in vivo bleeding/thrombosis models

    PMID:19641185 PMID:19824697

    Open questions at the time
    • Stoichiometry of Syk binding not yet directly measured
    • Developmental role not yet tested genetically
  5. 2010 High

    CLEC-2 knockout mice revealed that hemITAM signaling via Syk/SLP-76 on platelets is essential for embryonic blood–lymphatic separation, while biophysical studies confirmed 2:1 Syk:CLEC-2 stoichiometry and showed that hemITAM phosphorylation requires lipid raft translocation, actin polymerization, and ADP/TxA2 positive feedback.

    Evidence Constitutive and platelet-specific conditional KOs, fetal liver transplant, quantitative SPR/cross-linking/EM, lipid raft fractionation, pharmacological inhibitors

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

    Open questions at the time
    • Relative contributions of Syk versus Src in initiating versus amplifying signaling debated
    • How lipid raft translocation is triggered mechanistically unclear
    • Whether CLEC-2 has signaling-independent roles unknown
  6. 2012 High

    Beyond platelets, CLEC-2 was shown to regulate dendritic cell motility through RhoA inhibition and Rac1/Vav-dependent actin protrusions upon podoplanin engagement, while in platelets, CLEC-2 activation releases BMP-9 and TGF-β to inhibit lymphatic endothelial cell proliferation and tube formation.

    Evidence CLEC-2-deficient DCs, migration/actin dynamics assays, RhoA/Rac1 activity assays, platelet-specific KO, LEC functional assays

    PMID:22556408 PMID:22884313

    Open questions at the time
    • Whether DC and platelet CLEC-2 signaling pathways diverge at the level of Syk unclear
    • How BMP-9 is stored and released from platelet granules not defined
  7. 2013 High

    The physiological function of platelet CLEC-2 was extended to maintaining high endothelial venule integrity through podoplanin-dependent S1P release promoting VE-cadherin expression, and fucoidan was identified as an additional CLEC-2 agonist.

    Evidence Conditional KO with platelet rescue, S1P pathway analysis, VE-cadherin staining, fucoidan activation in CLEC-2 KO platelets

    PMID:23341451 PMID:23995678

    Open questions at the time
    • Whether S1P release is the sole downstream mediator of HEV maintenance not excluded
    • Fucoidan binding site on CLEC-2 unknown
  8. 2014 High

    Co-crystal structures of CLEC-2 with both podoplanin and rhodocytin revealed a shared non-canonical 'side' binding face utilizing arginine–acidic residue interactions, providing a structural explanation for ligand promiscuity, while super-resolution imaging showed Src/Syk-dependent CLEC-2/podoplanin clustering within 10 nm on platelet membranes.

    Evidence X-ray crystallography of two ligand complexes, dSTORM/FLIM-FRET, supported lipid bilayer with Syk−/− platelets

    PMID:25368330 PMID:25458834

    Open questions at the time
    • Full-length receptor structure including transmembrane and cytoplasmic domains not solved
    • Structural basis of higher-order clustering beyond dimers unknown
  9. 2015 High

    Multiple in vivo studies established CLEC-2/podoplanin as critical for cerebrovascular patterning, lymph node development, megakaryopoiesis (via Thpo production), venous thrombosis, and infection-driven thromboinflammation, while S100A13 was identified as an additional CLEC-2 ligand on vascular smooth muscle cells.

    Evidence Constitutive/conditional KOs (platelet-specific, Mk-specific, Nestin-Cre), IVC stenosis DVT model, anti-PDPN antibody, Salmonella infection model, SPR/protein array for S100A13, HSC transplant

    PMID:24532804 PMID:25908104 PMID:26418160 PMID:26552707 PMID:26571395 PMID:28104688

    Open questions at the time
    • Relative quantitative contributions of multiple CLEC-2 ligands in different vascular beds undefined
    • Mechanistic link between Mk CLEC-2 and Thpo transcription not fully resolved
    • S100A13 binding site not mapped
  10. 2017 High

    A hemITAM-dead knockin (Y7A) distinguished signaling-dependent from signaling-independent CLEC-2 functions: blood–lymphatic separation requires hemITAM signaling, whereas hemostasis/thrombosis also involves a structural/adhesive contribution independent of YXXL phosphorylation. Gq/PLCβ/PKCα/Src was defined as the positive feedback loop potentiating hemITAM phosphorylation.

    Evidence Y7A knockin mouse with anti-CLEC-2 Fab blockade, in vivo thrombosis models, Gq−/− platelets, pharmacological pathway dissection

    PMID:28705934 PMID:28835437

    Open questions at the time
    • Nature of signaling-independent adhesive mechanism unknown
    • Whether Gq feedback loop operates in non-platelet CLEC-2-expressing cells not tested
  11. 2018 High

    CLEC-2/podoplanin was shown to be essential for lung alveolar development via TGF-β-dependent myofibroblast differentiation, CD37 was identified as a tetraspanin partner controlling CLEC-2 membrane organization in DCs, and a small-molecule antagonist (Co-HP) binding a site distinct from podoplanin inhibited thrombosis and metastasis without bleeding.

    Evidence Platelet-specific and LEC-specific conditional KOs, CD37−/− DC functional assays and co-IP, Co-HP SPR/mutagenesis with in vivo thrombosis/metastasis models

    PMID:29853539 PMID:30185523 PMID:30190281

    Open questions at the time
    • How Co-HP binding inhibits signaling allosterically not structurally resolved
    • CD37 interaction interface not mapped
    • Lung phenotype in humans with CLEC-2 loss unknown
  12. 2019 High

    CLEC-2 activation by dengue virus triggers platelet extracellular vesicle release that activates innate immune receptors CLEC5A and TLR2 on neutrophils/macrophages, establishing a platelet-to-innate-immune amplification loop in viral thromboinflammation.

    Evidence In vitro platelet EV isolation, neutrophil/macrophage activation assays, dengue mouse model with CLEC5A/TLR2 blockade

    PMID:31160588

    Open questions at the time
    • Whether EV-mediated amplification applies to other viral infections not tested
    • Specific viral component engaging CLEC-2 not identified
  13. 2020 High

    Phosphoproteomic profiling of CLEC-2-activated platelets revealed 363 differentially phosphorylated tyrosine sites and identified novel signalosome components (DAPP1, Dok1/3, CASS4, FAK1, FES, JAK2), while in vivo studies showed platelet CLEC-2 impairs hepatic recovery after acute injury by suppressing TNF-α-driven neutrophil recruitment.

    Evidence MS-based phosphotyrosine proteomics with kinase inhibitors; CLEC-2 KO mice in APAP/CCl4 liver injury models with cytokine/neutrophil analysis

    PMID:31901221 PMID:32321925

    Open questions at the time
    • Functional validation of most novel signalosome components pending
    • Whether CLEC-2's liver injury role is podoplanin-dependent not directly tested
  14. 2021 High

    Btk was positioned as a critical node in CLEC-2 positive feedback in human (but not mouse) platelets, hemin was confirmed as a direct CLEC-2 and GPVI co-ligand relevant to rhabdomyolysis, and CLEC-2/podoplanin interaction on macrophages was shown to accelerate their emigration from inflamed peritoneum via ERM-mediated cytoskeletal remodeling.

    Evidence XLA patient platelets and ibrutinib/acalabrutinib treatment; SPR plus double-KO (CLEC-2/FcRγ) in RAKI model; platelet-specific CLEC-2 KO in peritonitis with recombinant CLEC-2-Fc and ERM studies

    PMID:31949019 PMID:33843987 PMID:34163489

    Open questions at the time
    • Species differences in Btk feedback not structurally explained
    • Hemin binding site on CLEC-2 not mapped
    • How CLEC-2 engagement on macrophages upregulates podoplanin/CD44 not mechanistically resolved
  15. 2022 High

    Cooperative signaling between CLEC-2 and GPIIb/IIIa was shown to trigger cerebral venous sinus thrombosis, demonstrating that CLEC-2 does not act in isolation but synergizes with integrin signaling for pathological thrombus formation in specific vascular beds.

    Evidence Antibody-induced CLEC-2 activation model, intravital transcranial microscopy, GPIIb/IIIa antagonist rescue

    PMID:39195988

    Open questions at the time
    • Molecular mechanism of CLEC-2/GPIIb/IIIa crosstalk not defined
    • Relevance to human CVT (e.g., vaccine-induced) not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of CLEC-2 including transmembrane and cytoplasmic domains, the structural basis of higher-order clustering beyond dimers, functional validation of newly identified signalosome components, the molecular nature of CLEC-2's signaling-independent adhesive role in hemostasis, and whether human CLEC-2 loss-of-function mutations cause developmental vascular disease.
  • No full-length receptor structure
  • No human genetic disease linked to CLEC1B mutations in the timeline
  • Signaling-independent adhesive mechanism molecularly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-109582 Hemostasis 6 R-HSA-1266738 Developmental Biology 6 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5
Partners
CD37ITGA2BLCP2PDPNPLCG2SYK
Complex memberships
CLEC-2 homodimer

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CLEC-2 (CLEC1B) was identified as the receptor for snake venom rhodocytin on platelets via rhodocytin affinity chromatography. Ligand binding causes tyrosine phosphorylation of a single YXXL motif in the CLEC-2 cytosolic tail, which is dependent on Src family kinases, and activates Syk and PLCgamma2. Activation is abolished in Syk-/- and PLCgamma2-/- murine platelets and partially reduced in LAT, SLP-76, and Vav1/Vav3-deficient platelets. Rhodocytin affinity chromatography, expression in cell lines, genetic knockout mice, phosphorylation assays, kinase inhibitors Blood High 16174766
2006 Crystal structure of the extracellular domain of human CLEC-2 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 confirmed the key residues involved in rhodocytin binding. X-ray crystallography, site-directed mutagenesis, surface plasmon resonance The Journal of biological chemistry High 17132623
2007 Podoplanin was identified as an endogenous ligand for CLEC-2 on platelets. The CLEC-2-podoplanin interaction 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. Flow cytometry binding assays, recombinant protein inhibition, deletion mutant analysis The Journal of biological chemistry High 17616532
2007 CLEC-2 and Dectin-1 signal through a novel YXXL-dependent pathway requiring both SH2 domains of Syk (despite having only a single YXXL motif), Src and Tec family kinases, and PLCgamma, with only partial dependence on SLP-76/BLNK adapters. The glycine residue directly upstream of the YXXL tyrosine in the DEDG sequence is critical for CLEC-2 signaling. Mutant cell line signaling assays, site-directed mutagenesis of YXXL and DEDG motifs, kinase inhibitors The Journal of biological chemistry High 17339324
2007 Molecular characterization of the podoplanin-CLEC-2 interaction: CLEC-2 deletion mutants (expressed as Fc chimeras) identified the podoplanin-recognition domain; a disialyl-core1-attached glycopeptide at Thr52 of podoplanin is specifically recognized by CLEC-2; the protein stereostructure of podoplanin is also critical for binding. Deletion mutant Fc chimeras, synthesized glycopeptides, in vitro binding assays, in vivo metastasis model Cancer science High 17944973
2008 Podoplanin on renal cells (HEK-293T and podocytes) was confirmed as a CLEC-2 ligand. Direct CLEC-2-podoplanin interaction measured by surface plasmon resonance showed an affinity of ~24.5 µM and was shown to be independent of glycosylation of CLEC-2. Surface plasmon resonance, recombinant protein binding, CLEC-2-transfected DT-40 B-cell activation assay The Biochemical journal High 18215137
2008 Crystal structure of rhodocytin (CLEC-2 ligand) solved at 2.4 Å; rhodocytin forms a non-disulfide-linked (αβ)2 tetramer with a concave binding surface complementary to the CLEC-2 binding interface, suggesting it clusters CLEC-2 receptors on the platelet surface to trigger signaling. X-ray crystallography, computational docking, surface electrostatic analysis Protein science High 18583525
2008 G6b-B, a platelet immunoglobulin receptor with two ITIM motifs, inhibits constitutive and agonist-induced signaling by CLEC-2 (and GPVI). Inhibition by G6b-B requires its conserved ITIM tyrosines and is independent of SHP1, SHP2, and SHIP phosphatases. NFAT reporter assay, mutagenesis, cell line signaling studies The Journal of biological chemistry Medium 18955485
2009 CLEC-2 is present as a non-disulfide-linked homodimer in resting platelets. This dimerization enables each Syk molecule to interact with two YXXL motifs (one from each CLEC-2 monomer), explaining how a hemITAM activates Syk normally requiring tandem YXXL. BRET, co-immunoprecipitation, analytical gel filtration, surface plasmon resonance, MALS, analytical ultracentrifugation Biochemistry High 19824697
2009 CLEC-2-deficient platelets (via anti-CLEC-2 antibody depletion) show normal adhesion under flow but severely defective aggregate formation in vitro and in vivo, resulting in increased bleeding times and protection from occlusive arterial thrombus formation, establishing CLEC-2 as essential for hemostasis and thrombosis. Antibody-mediated CLEC-2 depletion, intravital microscopy, in vitro flow chamber assays, bleeding time measurements Blood High 19641185
2009 CLEC-2 is expressed on murine peripheral blood neutrophils (not bone marrow or elicited neutrophils). On neutrophils, CLEC-2 mediates phagocytosis of antibody-coated beads and TNF-alpha production upon rhodocytin stimulation through its tyrosine-based cytoplasmic motif, recruiting Syk. Monoclonal antibody staining, chimeric receptor analysis, phagocytosis assay, cytokine ELISA, Syk recruitment assay Journal of immunology Medium 19299712
2010 CLEC-2-deficient mice (Clec-2-/- generated by gene targeting) are lethal at embryonic/neonatal stages with disorganized, blood-filled lymphatic vessels and severe edema. Fetal liver transplantation demonstrated that CLEC-2 is involved in thrombus stabilization in vitro and in vivo, potentially through homophilic interactions, without apparent increase in bleeding tendency. Gene knockout, fetal liver transplantation, intravital microscopy, laser-induced thrombosis The Journal of biological chemistry High 20525685
2010 Platelet CLEC-2 directly binds lymphatic endothelial cell podoplanin (PDPN), activating SLP-76 signaling. Genetic loss of CLEC-2 abolishes PDPN binding by platelets and causes embryonic lymphatic vascular defects; platelet-specific deletion of Slp-76 is sufficient to recapitulate the defect, establishing the platelet CLEC-2/SLP-76 pathway as essential for blood-lymphatic separation. Genetic knockout (CLEC-2-/-, platelet-specific PF4-Cre Slp-76 deletion), intravital and ex vivo imaging, flow cytometry Blood High 20363774
2010 Syk, but not the major platelet Src family kinases (Fyn, Lyn, Src) or CD148, is required for phosphorylation of the CLEC-2 hemITAM by rhodocytin. Src family kinases play critical roles downstream of Syk, regulating Syk activity and other effector proteins rather than initiating CLEC-2 phosphorylation directly. Syk-/- and Src kinase-deficient mouse platelets, kinase inhibitor PP2, western blotting of phosphorylation The Journal of biological chemistry High 21098033
2010 CLEC-2 activates Syk through dimerization: phosphorylated CLEC-2 hemITAM recruits Syk in a 2:1 stoichiometry via its tandem SH2 domains. CLEC-2 exists as a dimer in resting platelets and forms larger complexes upon activation, as confirmed by cross-linking and electron microscopy. Peptide pulldown, surface plasmon resonance, quantitative western blotting, tryptophan fluorescence, cross-linking, electron microscopy Blood High 20154219
2010 CLEC-2 hemITAM phosphorylation requires translocation to lipid rafts upon ligand engagement; this translocation and the subsequent phosphorylation are also critically dependent on actin polymerization, Rac1 activation, and release of ADP and TxA2 as secondary mediators. In contrast, GPVI-ITAM phosphorylation is independent of these events. Sucrose gradient ultracentrifugation, methyl-beta-cyclodextrin treatment, actin polymerization inhibitors, Rac1 inhibition, ADP/TxA2 pathway inhibitors Blood High 20154214
2011 Conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage causes defects in brain vascular and lymphatic development. Platelets (but not platelet releasate) directly modulate migration and intercellular adhesion of lymphatic endothelial cells through a CLEC-2- and Syk-dependent pathway. Conditional knockout (Cre-lox), in vitro lymphatic endothelial cell migration/adhesion assays, releasate vs. cell contact experiments Blood High 22186994
2012 Platelet CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells (LECs). Activated platelets release BMP-9 (present in platelet granules), which plays a key role in inhibiting LEC tube formation; TGF-beta and PF4 also inhibit proliferation/migration. Platelet-specific CLEC-2 knockout (Cre-lox), in vitro LEC migration/proliferation/tube formation assays, BMP-9 identification in platelets The Journal of biological chemistry High 22556408
2012 CLEC-2 engagement by podoplanin in dendritic cells (DCs) rearranges the actin cytoskeleton to promote DC motility. CLEC-2 activation triggers cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation, and F-actin-rich protrusions via Vav signaling and Rac1 activation, enabling DC migration along stromal surfaces and entry into lymphatics. CLEC-2-deficient DCs, DC migration assays, RhoA/Rac1 activity assays, actin dynamics imaging Immunity High 22884313
2012 The triacidic amino acid sequence (DEDG) upstream of the YXXL hemITAM in CLEC-2 is required for hemITAM phosphorylation; mutation of these acidic residues abolishes Syk-dependent signaling. Syk-mediated signaling is restricted to Syk (not Zap-70) in hemITAM receptors. Site-directed mutagenesis, Syk/Zap-70-deficient cell lines, SPR, phosphorylation assays The Journal of biological chemistry High 23264619
2013 Podoplanin expressed on fibroblastic reticular cells (FRCs) surrounding high endothelial venules (HEVs) activates platelet CLEC-2. CLEC-2-mediated platelet activation induces release of sphingosine-1-phosphate (S1P) from platelets, which promotes VE-cadherin expression on HEVs, maintaining vascular integrity. Infusion of wild-type platelets restored HEV integrity in Clec-2-deficient mice. Conditional knockout mice, platelet infusion rescue, S1P pathway analysis, VE-cadherin staining, ex vivo HEV treatment Nature High 23995678
2013 Fucoidan (a sulfated polysaccharide) is a novel CLEC-2 agonist; fucoidan-induced platelet activation is abolished in platelet-specific CLEC-2 knockout platelets, occurs via Src and Syk kinase-dependent signaling, and is largely independent of the GPVI/FcRgamma pathway. CLEC-2 platelet-specific KO, aggregometry, tyrosine phosphorylation assays, FcRgamma-/- mice The Journal of biological chemistry High 23341451
2014 Crystal structures of CLEC-2 in complex with podoplanin glycopeptide and rhodocytin reveal that both ligands bind to the non-canonical 'side' face of CLEC-2. A common interaction mode involves consecutive acidic residues on ligands interacting with arginine residues on CLEC-2; the second binding site differs: sialic acid carboxyl from podoplanin vs. rhodocytin C-terminus interact differently. X-ray crystallography of CLEC-2 complexes with podoplanin peptide and rhodocytin Structure High 25458834
2014 Podoplanin regulates actomyosin contractility in fibroblastic reticular cells (FRCs) through the CLEC-2/podoplanin axis. Under resting conditions, PDPN endows FRCs with contractile function. Upon inflammation, CLEC-2 on mature DCs attenuates PDPN-mediated contractility, resulting in FRC relaxation, reduced tissue stiffness, and an expanded reticular network with enhanced immunity. Collagen gel contraction assay, FRC co-culture with CLEC-2-expressing DCs, stiffness measurements, podoplanin loss-of-function Nature immunology High 25347465
2014 CLEC-2 signaling via Src and Syk kinases promotes platelet adhesion to lymphatic endothelial cells and clustering of CLEC-2 with podoplanin on supported lipid bilayers. CLEC-2/podoplanin clusters migrate to the center of the platelet and are within 10 nm of one another; disrupted by Src/Syk inhibition. CLEC-2 clusters also observed by dSTORM on immobilized podoplanin. Supported lipid bilayer with mobile podoplanin, FLIM-FRET, dSTORM, Src/Syk kinase inhibitors, Syk-/- mouse platelets The Journal of biological chemistry High 25368330
2014 CLEC-2 is required for development and maintenance of lymph nodes. Constitutive CLEC-2 deletion impairs lymphatic endothelial cell proliferation resulting in absent LNs; platelet-specific CLEC-2 deletion leads to blood-filled LNs and fibrosis. Platelet CLEC-2 is required for LN integrity and immune cell recirculation. Constitutive and platelet-specific (PF4-Cre) CLEC-2 knockout, bone marrow chimeras, immunization experiments Blood High 24532804
2015 CLEC-2 in megakaryocytes mediates production of thrombopoietin (Thpo) and other factors via the Syk/Lcp2/Plcg2 signaling axis. Megakaryocyte-specific CLEC-2 deletion (Clec2MkΔ/Δ) reduces Thpo in megakaryocytes, decreases HSC quiescence and repopulation potential, and causes extramedullary hematopoiesis; recombinant Thpo administration restores HSC potential. Megakaryocyte-specific conditional KO, knockdown of signaling molecules in cultured Mks, recombinant Thpo rescue, HSC transplantation assays The Journal of experimental medicine High 26552707
2015 CLEC-2 drives venous thrombosis through podoplanin interaction; platelet-specific or inducible CLEC-2 deletion protects mice from DVT in IVC stenosis model. Podoplanin is expressed in the IVC wall near the abluminal endothelium and is upregulated in thrombus-bearing vessels. Anti-podoplanin neutralizing antibody reduces thrombus size. Inducible and platelet-specific CLEC-2 KO, IVC stenosis DVT model, platelet transfusion, anti-podoplanin antibody treatment, intravital imaging Blood High 28104688
2015 Podoplanin-positive bone marrow periarteriolar stromal cells (BM FRC-like cells) promote megakaryocyte growth and proplatelet formation through CLEC-2/podoplanin interaction. This interaction induces BM FRC-like cells to secrete CCL5, which facilitates proplatelet formation. Platelet/Mk-specific CLEC-2 conditional KO, in vitro megakaryocyte-BM FRC co-culture, recombinant PDPN stimulation, CCL5 ELISA, immunohistochemistry Blood High 26796360
2015 Podoplanin and CLEC-2 control cerebrovascular patterning during development. Constitutive or platelet-specific deletion of CLEC-2 causes tortuous, aberrantly patterned cerebral vessels at E10.5 with large hemorrhages and defective pericyte recruitment. Nestin-Cre-driven deletion of podoplanin on neural progenitors also causes cerebral hemorrhaging. Constitutive and conditional (platelet-specific, neural progenitor-specific Nestin-Cre) knockout mice, 3D light-sheet microscopy, immunofluorescence, electron microscopy Blood High 25908104
2015 S100A13 was identified as a CLEC-2 ligand in vascular smooth muscle cells (VSMCs) using protein array and Biacore analysis. VSMCs stimulate platelet granule release and support thrombus formation under flow in a CLEC-2-dependent manner. S100A13 is released under oxidative stress and expressed in atherosclerotic lesions. Recombinant CLEC-2 binding studies, protein array, surface plasmon resonance (Biacore), CLEC-2-deficient mice, flow chamber thrombosis, FeCl3 thrombosis model PloS one Medium 26418160
2015 During bacterial infection (Salmonella), inflammation triggers upregulation of podoplanin on podoplanin-expressing monocytes and Kupffer cells at perivascular sites via IFN-gamma, which then activates platelet CLEC-2 to drive thrombus formation independently of classical GPVI-mediated activation. TLR4 and IFN-gamma are required upstream of this process. Salmonella infection mouse model, intravital liver imaging, cell depletion, TLR4/IFN-gamma/CLEC-2 genetic/antibody-mediated deletion, podoplanin immunostaining The Journal of clinical investigation High 26571395
2017 A CLEC-2 knockin mouse expressing CLEC-2 with a non-signaling hemITAM (Y7A KI) recapitulates 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' fragments revealed a hemITAM signaling-independent role for CLEC-2 in hemostasis and thrombosis, suggesting a structural/adhesive contribution. Knockin mouse (Y7A hemITAM mutation), anti-CLEC-2 Fab' functional blockade, in vivo thrombosis models, tail bleeding time Blood High 28835437
2017 Platelet-specific CLEC-2 deletion leads to enhanced systemic inflammation and accelerated organ injury in sepsis models (LPS and cecal ligation/puncture). 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, suggesting podoplanin activation on macrophages drives the anti-inflammatory action. Platelet-specific CLEC-2 KO, LPS and CLP sepsis models, immune cell counts, cytokine measurement, pharmacological inhibition Nature communications High 29269852
2017 Gq signaling potentiates CLEC-2 signaling via the PLCβ-PKCα pathway, which regulates Src family kinase activity upstream of CLEC-2 hemITAM phosphorylation. TxA2 (via Gq) specifically potentiates CLEC-2 receptor tyrosine phosphorylation and downstream Syk/PLCgamma2 phosphorylation. Gq inhibitor (UBO-QIC), Gq-/- mouse platelets, pharmacological pathway dissection, western blotting of phosphorylation The Journal of biological chemistry High 28705934
2018 Cobalt hematoporphyrin (Co-HP) directly binds to CLEC-2 at residues N120, N210, and K211 (confirmed by CLEC-2 mutant analysis), which are distinct from the previously known podoplanin-binding sites. Co-HP inhibits CLEC-2-mediated platelet aggregation and suppresses tumor metastasis and arterial/venous thrombosis in vivo without prolonging bleeding time. SPR, molecular docking, CLEC-2 mutant analysis, in vitro platelet aggregation, in vivo thrombosis and metastasis models Blood advances High 30190281
2018 Platelets play an essential role in lung development through CLEC-2/podoplanin interaction. Platelet-specific CLEC-2 deletion in mice causes lung malformation (absence of alveolar duct myofibroblasts) and neonatal lethality. LEC-specific podoplanin deletion phenocopies this defect; CLEC-2/podoplanin interaction on LECs stimulates adMYF differentiation of lung mesothelial cells via TGF-beta signaling. Platelet-specific and LEC-specific conditional knockout mice, histology, immunostaining, TGF-beta pathway analysis, thrombocytopenia model Blood High 29853539
2018 Recombinant rhodocytin forms a heterooctamer (four α- and β-subunits); Asp4 in the α-subunit is required for CLEC-2 binding. An inhibitory mutant rhodocytin (αWTβK53A/R56A forming a heterotetramer) binds CLEC-2 without inducing platelet aggregation and blocks CLEC-2-podoplanin-dependent platelet aggregation and experimental lung metastasis. Recombinant protein expression (CHO cells), blue native PAGE, flow cytometry, light transmission aggregometry, in vivo lung metastasis model Journal of thrombosis and haemostasis High 29488681
2018 Tetraspanin CD37 controls CLEC-2 membrane organization in dendritic cells. A specific CLEC-2-CD37 interaction was identified; CD37-/- myeloid cells have reduced surface CLEC-2. Loss of CD37 impairs CLEC-2 recruitment to podoplanin, DC adhesion, migration velocity, actin protrusion formation in 3D collagen, and CLEC-2-dependent inhibition of FRC actomyosin contractility. Co-immunoprecipitation, CD37-/- DCs, DC migration assays, microcontact printing, 3D collagen matrix assays, FRC contraction assay Journal of cell science High 30185523
2019 Dengue virus activates platelets via CLEC-2 to release extracellular vesicles (exosomes and microvesicles). These CLEC-2-induced EVs activate CLEC5A and TLR2 on neutrophils and macrophages, triggering NET formation and proinflammatory cytokine release. Simultaneous blockade of CLEC5A and TLR2 increased survival from 30 to 90% in dengue-infected mice. In vitro platelet activation, EV isolation, neutrophil/macrophage activation assays, in vivo dengue mouse model, CLEC5A/TLR2 blockade Nature communications High 31160588
2019 Shed CLEC-2 is generated independently of ADAM10/17 (which shed GPVI) and is partially generated by MMP-2. CLEC-2 is released as a shed fragment or as a whole molecule associated with platelet microparticles (MP-CLEC-2), unlike GPVI which is not associated with microparticles under normal conditions. Metalloproteinase inhibitors/stimulators, anti-domain-specific antibodies, microparticle isolation, immunoblotting International journal of hematology Medium 31165998
2020 Platelet CLEC-2 signaling impairs hepatic recovery after acetaminophen-induced acute liver failure by suppressing TNF-alpha production and reducing reparative hepatic neutrophil recruitment. Blocking platelet CLEC-2 signaling enhances liver recovery by increasing TNF-alpha levels which drive beneficial neutrophil responses. CLEC-2-deficient mice, APAP and CCl4 liver injury models, neutrophil depletion, cytokine measurement, flow cytometry, human liver samples Nature communications High 32321925
2021 CLEC-2 exists as a monomer and homo-dimer in resting platelets and forms higher-order oligomers following ligand activation. Syk binding to phosphorylated hemITAM is mediated by tandem SH2 domains binding to PIP2/PIP3 at the membrane. Low-level Syk activity in resting platelets (due to Src family kinase phosphorylation) is amplified by receptor clustering, which disturbs the kinase-phosphatase equilibrium to trigger hemITAM phosphorylation. Structural analysis, membrane lipid binding studies, review of published data integrating biophysical and biochemical evidence Platelets Medium 33819136
2021 Low concentrations of the Btk inhibitor ibrutinib (and acalabrutinib) selectively block CLEC-2-mediated platelet activation and tyrosine phosphorylation including Syk and PLCgamma2 in human platelets, while only delaying GPVI responses. This differential effect is explained by Btk's positive feedback role in CLEC-2 signaling (via ADP/TxA2/P2Y12/TP receptors), which is not present in mouse platelets. Human platelets with ibrutinib/acalabrutinib, XLA patient platelets (Btk-deficient), aggregometry, phosphorylation assays, mouse in vivo thrombosis Haematologica High 31949019
2021 Platelet CLEC-2 reduces inflammatory macrophage accumulation during peritonitis. CLEC-2 engagement of podoplanin on macrophages (upregulated during inflammation) accelerates actin rearrangement and macrophage migration by increasing podoplanin and CD44 expression and their interaction with ERM proteins, promoting macrophage emigration to draining lymph nodes. Platelet-specific CLEC-2 KO, recombinant CLEC-2-Fc, LPS peritonitis model, macrophage migration assays, ERM protein interaction studies, flow cytometry Frontiers in immunology High 34163489
2021 Hemin (free heme) directly binds to both CLEC-2 and GPVI on platelets (confirmed by western blotting and SPR), activating platelet aggregation via SYK and PLCgamma2 phosphorylation. Double knockout of CLEC-2 and FcRgamma (GPVI-equivalent) nearly abolishes hemin-induced platelet aggregation and attenuates rhabdomyolysis-induced acute kidney injury. SPR binding, western blotting, CLEC-2-depleted and FcRgamma-/- mice (single and double KO), RAKI mouse model, in vitro MET formation Blood advances High 33843987
2022 Cooperative signaling between CLEC-2 and GPIIb/IIIa triggers cerebral venous sinus thrombosis (CVT)-like syndrome in mice. INU1-Fab-induced CLEC-2 signaling combined with GPIIb/IIIa activation causes rapid CVT. Interfering with CLEC-2 signaling or inhibiting GPIIb/IIIa completely blocked platelet activation and CVT; blocking GPIIb/IIIa after symptom onset protected against death. Antibody-induced CLEC-2 signaling model, intravital transcranial microscopy, CLEC-2 signaling inhibition, GPIIb/IIIa antagonist treatment Nature cardiovascular research High 39195988
2015 Targeted downregulation of platelet CLEC-2 by antibody INU1 occurs through Src family kinase-dependent receptor internalization (not Syk-dependent), presumably followed by intracellular degradation. In platelet-specific Syk-deficient mice, INU1-induced CLEC-2 internalization was fully preserved while the associated thrombocytopenia was largely prevented, mechanistically uncoupling the two processes. Anti-CLEC-2 antibody (INU1) treatment, Src family kinase inhibitors, platelet-specific Syk-deficient mice, receptor internalization assays in vitro and in vivo Blood High 25795918
2006 Platelets express CLEC-2, which binds HIV-1 independently of the viral envelope protein, facilitating HIV-1 capture by platelets. CLEC-2 and DC-SIGN together are required for efficient HIV-1 binding; captured HIV-1 remains infectious for several days, suggesting CLEC-2 may facilitate HIV-1 dissemination. Flow cytometry binding assays, DC-SIGN and CLEC-2 inhibitors, platelet HIV-1 capture assays, infectivity assays Journal of virology Medium 16940507
2015 Podoplanin/CLEC-2 signaling regulates keratinocyte migration during wound healing. CLEC-2 addition and podoplanin knockdown both inhibit keratinocyte migration. CLEC-2 downregulates RhoA activity and upregulates E-cadherin in keratinocytes, providing a molecular mechanism for the regulation of migration. podoplanin siRNA in NHEK cells, CLEC-2 protein addition, wound healing and transwell migration assays, RhoA activity assay, E-cadherin immunostaining The American journal of pathology Medium 26597882
2020 Phosphoproteomic analysis of rhodocytin-activated platelets identified 363 differentially phosphorylated tyrosine residues. Syk phosphorylation at Tyr525+526 occurs even with ADP and TxA2 pathway inhibitors, while Src-pTyr419 and PLCgamma2-pTyr759 require ADP/TxA2 feedback. Novel components of the CLEC-2 signalosome identified include adaptors DAPP1, Dok1/3, CASS4, Nck1/2, kinases FAK1, FES, FGR, JAK2, SHIP2, and membrane proteins G6F, JAM-A, PECAM-1, TLT-1. Mass spectrometry-based phosphotyrosine proteomics, 2D-DIGE, kinase inhibitors, Ca2+ mobilization assays Thrombosis and haemostasis Medium 31901221

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 397 17616532
2005 A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 392 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 258 23995678
2019 Functional significance of the platelet immune receptors GPVI and CLEC-2. The Journal of clinical investigation 246 30601137
2012 Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 235 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 227 17944973
2014 The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nature immunology 219 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 199 20525685
2019 Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nature communications 190 31160588
2009 CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 174 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 165 23991201
2019 Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin. Blood 154 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 143 28104688
2015 Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets. The Journal of clinical investigation 134 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 129 22556408
2017 The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. Nature communications 119 29269852
2010 CLEC-2 activates Syk through dimerization. Blood 115 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 107 26552707
2014 CLEC-2 expression is maintained on activated platelets and on platelet microparticles. Blood 100 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) 96 19299712
2014 A platform of C-type lectin-like receptor CLEC-2 for binding O-glycosylated podoplanin and nonglycosylated rhodocytin. Structure (London, England : 1993) 93 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 90 19422460
2010 Syk-dependent phosphorylation of CLEC-2: a novel mechanism of hem-immunoreceptor tyrosine-based activation motif signaling. The Journal of biological chemistry 87 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
2011 CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses. European journal of immunology 72 21728173
2020 The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure. Nature communications 68 32321925
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
2010 Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac. Blood 59 20154214
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 58 25368330
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 55 28839100
2013 Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2). The Journal of biological chemistry 54 23341451
2018 Cobalt hematoporphyrin inhibits CLEC-2-podoplanin interaction, tumor metastasis, and arterial/venous thrombosis in mice. Blood advances 53 30190281
2016 Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2. Blood 53 26796360
2013 Platelet receptors activated via mulitmerization: glycoprotein VI, GPIb-IX-V, and CLEC-2. Journal of thrombosis and haemostasis : JTH 53 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
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
2014 Complexity and Diversity of the NKR-P1:Clr (Klrb1:Clec2) Recognition Systems. Frontiers in immunology 49 24917862
2018 Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction. Blood 48 29853539
2009 The platelet receptor CLEC-2 is active as a dimer. Biochemistry 48 19824697
2021 The Role of CLEC-2 and Its Ligands in Thromboinflammation. Frontiers in immunology 47 34177942
2008 G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2. The Journal of biological chemistry 47 18955485
2015 Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis. PloS one 42 26418160
2021 Heme activates platelets and exacerbates rhabdomyolysis-induced acute kidney injury via CLEC-2 and GPVI/FcRγ. Blood advances 41 33843987
2021 Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment. Frontiers in immunology 41 34987523
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
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 40 29488681
2017 Platelet CLEC-2: Roles Beyond Hemostasis. Seminars in thrombosis and hemostasis 40 28992650
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
2018 Roles of the CLEC-2-podoplanin interaction in tumor progression. Platelets 37 29863945
2017 CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 37 28835437
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 35 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 34 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
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 Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization. Blood 31 25795918
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
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
2008 Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2. Journal of thrombosis and haemostasis : JTH 27 18826392
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
2021 The structure of CLEC-2: mechanisms of dimerization and higher-order clustering. Platelets 22 33819136
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
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 21 37473844
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
2019 Elevated plasma levels of soluble C-type lectin-like receptor 2 (CLEC2) in patients with thrombotic microangiopathy. Thrombosis research 20 30978634
2022 Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP. Blood 19 35157766
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
2021 CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis. Frontiers in immunology 18 34163489
2020 Lymphatic blood filling in CLEC-2-deficient mouse models. Platelets 17 32129691
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 17 24736277
2022 CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear. Thrombosis and haemostasis 16 35817083
2019 Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin. Hematology. American Society of Hematology. Education Program 16 31808911
2008 Thrombomodulation via CLEC-2 targeting. Current opinion in pharmacology 16 19091630
2020 Platelet CLEC-2 and lung development. Research and practice in thrombosis and haemostasis 15 32548549
2016 New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2. Thrombosis journal 15 27766053