Clec-2

BACKGROUND: C-type lectin domain family 1 member B (CLEC1B, encoding the CLEC-2 protein), a member of the C-type lectin superfamily, is a type II transmembrane receptor involved in platelet activation, angiogenesis, and immune and inflammatory responses. However, data regarding its function and clinical prognostic value in hepatocellular carcinoma (HCC) remain scarce. METHODS: The expression of CLEC1B was explored using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases...

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of infancy which is commonly associated with a life-threatening thrombocytopenic condition, Kasabach-Merritt phenomenon (KMP). Platelet CLEC-2 - tumor podoplanin interaction is considered as the key mechanism of platelet clearance in these patients. Here we aimed to assess platelet functionality in such patients. Three groups by 6-9 children were enrolled: a) with KHE/KMP without hematologic response to therapy (HR), b) with KHE/KMP with HR, and c) healthy children...

Upon initial immune challenge, dendritic cells (DCs) migrate to lymph nodes and interact with fibroblastic reticular cells (FRCs) via C-type lectin-like receptor 2 (CLEC-2). CLEC-2 binds to the membrane glycoprotein podoplanin (PDPN) on FRCs, inhibiting actomyosin contractility through the FRC network and permitting lymph node expansion. The hyaluronic acid receptor CD44 is known to be required for FRCs to respond to DCs but the mechanism of action is not fully elucidated. Here, we use DNA-PAINT, a quantitative single molecule super-resolution technique, to visualize and quantify how PDPN clustering is regulated in the plasma membrane of FRCs...

To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry Leishmania antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism underlying this defective DC migration is not yet fully understood. Here, we demonstrate that L. donovani infection impaired the lymph node homing ability of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression. L...

INTRODUCTION:  Hemolysis results in release of free hemoglobin and hemin liberation from erythrocytes. Hemin has been described to induce platelet activation and to trigger thrombosis. METHODS:  We evaluated the effect of hemin on platelet function and surface expression of the platelet collagen receptor glycoprotein VI (GPVI). Isolated platelets were stimulated with increasing concentrations of hemin. RESULTS:  We found that hemin strongly enhanced platelet activation, aggregation, and aggregate formation on immobilized collagen under flow...

CLEC-2 is a target for a new class of antiplatelet agent. Clustering of CLEC-2 leads to phosphorylation of a cytosolic YxxL and binding of the tandem SH2 domains in Syk, crosslinking two receptors. We have raised 48 nanobodies to CLEC-2 and crosslinked the most potent of these to generate divalent and tetravalent nanobody ligands. Fluorescence correlation spectroscopy (FCS) was used to show that the multivalent nanobodies cluster CLEC-2 in the membrane and that clustering is reduced by inhibition of Syk. Strikingly, the tetravalent nanobody stimulated aggregation of human platelets, whereas the divalent nanobody was an antagonist...

As a specific lymphatic marker and a key ligand of C-type lectin-like receptor 2 (CLEC-2), podoplanin (Pdpn) is involved in various physiological and pathological processes such as growth and development, respiration, blood coagulation, lymphangiogenesis, angiogenesis, and inflammation. Thrombotic diseases constitute a major cause of disability and mortality in adults, in which thrombosis and inflammation play a crucial role. Recently, increasing evidence demonstrates the distribution and function of this glycoprotein in thrombotic diseases such as atherosclerosis, ischemic stroke, venous thrombosis, ischemic-reperfusion injury (IRI) of kidney and liver, and myocardial infarction...

The receptor protein CLEC-2 on platelet membranes is the target of the endogenous ligand podoplanin found on cancer cells and of rhodocytin, a snake venom component of the Malayan pit viper Calloselasma rhodostoma. Ligand binding results in platelet activation, increased blood coagulation and thrombosis. In an effort to isolate rhodocytin, we have purified CLEC-2 as bait from E. coli. Affinity captured rhodocytin interacted with mammalian CLEC-2 and stimulated platelet aggregation in a dose dependent manner...

OBJECTIVE: To investigate the in vivo intervention and relative mechanism of Genistein (GEN) on tumor-associated inflammatory and tumor thrombophilia in lymphoma-bearing mice. METHODS: Forty female Balb/c mice aged 5-6 weeks were injected with murine-derived Pro B-cell lymphoma cell line 38B9 to establish a lymphoma mouse model, which was randomly divided into control group, tumor-bearing group, GEN drug intervention group and cyclophosphamide (CTX）drug intervention group...

INTRODUCTION: Podoplanin (PDPN) is known to induce platelet aggregation via interacting with the C-type lectin-like receptor-2 on platelets and is involved in postoperative venous thromboembolism (VTE) formation. In this study, we investigate the correlation between soluble C-type lectin-like receptor (sCLEC-2) levels and PDPN expression in patients with high grade gliomas and the relationship between sCLEC-2 levels and the occurrence of VTE. MATERIALS AND METHODS: Forty-four patients harboring high grade gliomas, treated surgically at the Department of Neurosurgery, Niigata University from April 2018 to August 2020, were included...

Podoplanin (PDPN) is intensely expressed on the podocyte membrane in an evolutionally conserved manner. CLEC-2, the endogenous ligand of PDPN, is highly expressed in platelets and also exists in a soluble form in plasma. Normally, podocytes are sequestered from CLEC-2, but when the glomerular barrier is injured, podocytes gain access to CLEC-2. We tested the effects of CLEC-2 in podocytes in vitro and in vivo. Cultured podocytes treated with Fc-CLEC-2 demonstrated that CLEC-2 induced the dephosphorylation of ezrin, radixin, and moesin (ERM) proteins...

C-type lectin receptors (CLRs) elicit immune responses upon recognition of glycoconjugates present on pathogens and self-components. While Dectin-1 is the best-characterized CLR recognizing b-glucan on pathogens, the endogenous targets of Dectin-1 are not fully understood. Herein, we report that human Dectin-1 is a ligand for CLEC-2, another CLR expressed on platelets. Biochemical analyses revealed that Dectin-1 is a mucin-like protein as its stalk region is highly O -glycosylated. A sialylated core 1 glycan attached to the EDxxT motif of human Dectin-1, which is absent in mouse Dectin-1, provides a ligand moiety for CLEC-2...

The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling...

Podoplanin is a small mucin-like glycoprotein involved in several physiological and pathological processes in the brain including development, angiogenesis, tumors, ischemic stroke and other neurological disorders. Podoplanin expression is upregulated in different cell types including choroid plexus epithelial cells, glial cells, as well as periphery infiltrated immune cells during brain development and neurological disorders. As a transmembrane protein, podoplanin interacts with other molecules in the same or neighboring cells...

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BACKGROUND: As a transmembrane protein, C-type lectin-like receptor 2 (CLEC-2) is mainly expressed on platelets and released into plasma after platelet activation. Activated platelets participate in the regulation of innate immune cells. Patients with different microsatellite statuses have distinct immune profiles. This study aimed to investigate the association of plasma CLEC-2 levels with microsatellite status among colorectal cancer (CRC) patients. METHODS: A cross-sectional analysis of 430 CRC patients from Harbin Medical University Cancer Hospital was conducted...

Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural properties and collectively determine tissue mechanics of lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive expansion upon immune challenge. We find that in murine models of immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds...

Podoplanin (PDPN) promotes platelet aggregation and activation by interacting with C-type lectin-like receptor 2(CLEC-2) on platelets. The interaction between the upregulated PDPN and platelet CLEC-2 stimulates venous thrombosis. PDPN was identified as a risk factor for coagulation and thrombosis in inflammatory processes. Hypercoagulability is defined as the tendency to develop thrombosis according to fibrinogen and/or D dimer levels. Nephrotic syndrome is also considered to be a hypercoagulable state. The aim of this study is to investigate the association of soluble PDPN/CLEC-2 with hypercoagulability in nephrotic syndrome...

All irreversible Bruton tyrosine kinase (Btk) inhibitors including ibrutinib and acalabrutinib induce platelet dysfunction and increased bleeding risk. New reversible Btk inhibitors were developed, like MK-1026. The mechanism underlying increased bleeding tendency with Btk inhibitors remains unclear. We investigated the effects of ibrutinib, acalabrutinib and MK-1026 on platelet function in healthy volunteers, patients and Btk-deficient mice, together with off-target effects on tyrosine kinase phosphorylation...