C-type lectin-like receptor 2 (CLEC-2) is a 32 kDa, type II transmembrane glycoprotein and member of the C-type lectin-like family of receptors (1-4). CLEC-2 consists of a 33 amino acid (aa) cytoplasmic domain, a 21 aa transmembrane region, and a 175 aa extracellular domain (SwissProt # Q9P126). The cytoplasmic domain contains multiple threonine and serine residues which are sites of potential phosphorylation, and a YXXL (Tyr-Xaa-Xaa-Leu) motif through which CLEC-2 does its signaling (2, 4-5). Ligand binding and cross-linking of CLEC-2 induces Src kinase-dependent tyrosine phosphorylation of the YXXL sequence, inducing activation of the tyrosine kinase Syk and initiation of a signaling pathway that culminates in activation of phospholipase C gamma 2 (2, 5). The extracellular domain contains three potential sites of N-linked glycosylation, and a single carbohydrate recognition domain (CRD) which shows conservation of six cysteine residues (1, 6). Unlike most other members of the C-type lectin-like family of receptors, CLEC-2's CRD lacks the amino acid residues that are crucial for Ca2 ⁺-dependent carbohydrate binding, making it a non-classical C-type lectin receptor (1, 6). A splicing variant at aa 22-55 produces two isoforms for CLEC-2. Isoform 1 is the longer protein, and in isoform 2, an alanine residue is substituted for aa 22-55. Human CLEC-2 shares 63% aa sequence identity with mouse CLEC-2. CLEC-2 is expressed preferentially in liver, and is also detected in myeloid cells (monocytes, dendritic cells, and granulocytes) (1), platelets, and megakaryocytes (4). CLEC-2 is the receptor for the platelet-aggregating snake venom protein rhodocytin (3 - 4) and the molecule podoplanin, a transmembrane sialoglycoprotein that, when bound to CLEC-2, is involved in platelet aggregation, tumor metastasis, and lymphatic vessel formation (2, 7). CLEC-2 has also been shown to enhance infectivity of HIV-1 by mediating HIV-1 attachment and transfer by CLEC-2 transfected cells and platelets (8).