Structures of CLEC-2 and podoplanin. (A) CLEC-2 structure and its signal transduction pathway. CLEC-2 is cross-linked by podoplanin (endogenous ligand) or by rhodocytin (a platelet-activating snake venom) and undergoes tyrosine phosphorylation of hemi-ITAM (single YITL motif) by the Src family kinases. Then, the tyrosine kinase Syk binds to the phosphorylated ITAM motifs via its Src homology 2 (SH2) domains, which further increases Syk kinase activity. Syk phosphorylates adaptor proteins, LAT and SLP-76, which further activates downstream signaling molecules, including Bruton tyrosine kinase (Btk) and PLCγ2. PLCγ2 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to generate diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3), which leads to protein kinase C (PKC) activation and increase in Ca²⁺ mobilization from the open canalicular system (corresponding to endoplasmic reticulum), respectively. (B) Podoplanin structure. Podoplanin contains 4 platelet aggregation–stimulating (PLAG) domains, which are tandemly repeated and highly conserved. The podoplanin cytoplasmic domain is constitutively associated with ezrin/radixin/moesin (ERM) protein. Podoplanin clustering leads to functional effects through regulation of the actin cytoskeleton through ERM. pY, phosphorylated tyrosine.