Novel platelet activation receptor CLEC-2: from discovery to prospects

C-type lectin-like receptor 2 (CLEC-2) has been identified as a receptor for the platelet activating snake venom rhodocytin. CLEC-2 elicits powerful platelet activation signals in conjunction with Src, Syk kinases, and phospholipase Cγ2, similar to the collagen receptor glycoprotein (GP) VI/FcRγ-chain complex. In contrast to GPVI/FcRγ, which initiates platelet activation through the tandem YxxL motif immunoreceptor tyrosine-based activation motif (ITAM), CLEC-2 signals via the single YxxL motif hemi-ITAM. The endogenous ligand of CLEC-2 has been identified as podoplanin, which is expressed on the surface of tumour cells and facilitates tumour metastasis by inducing platelet activation. Studies of CLEC-2-deficient mice have revealed several physiological roles of CLEC-2. Podoplanin is also expressed in lymphatic endothelial cells as well as several other cells, including type I alveolar cells and kidney podocytes, but is absent from vascular endothelial cells. In the developmental stages, when the primary lymph sac is derived from the cardinal vein, podoplanin activates platelets in lymphatic endothelial cells by binding to CLEC-2, which facilitates blood/lymphatic vessel separation. Moreover, CLEC-2 is involved in thrombus stabilisation under flow conditions in part through homophilic interactions. However, the absence of CLEC-2 does not significantly increase bleeding tendency. CLEC-2 may be a good target protein for novel anti-platelet drugs or anti-metastatic drugs having therapeutic and preventive effects on arterial thrombosis and cancer, the primary causes of mortality in developed countries. In this article, we review the mechanisms of signal transduction, structure, expression, and function of CLEC-2.