The role of CLEC-2 in and beyond the vasculature

C-type lectin-like receptor 2 (CLEC-2) is a glycoprotein expressed on the surface of platelets that induces platelet activation including aggregation. Binding of the endogenous ligand podoplanin or the exogenous ligand rhodocytin to CLEC-2 induces tyrosine phosphorylation of the hemITAM motif expressed in its cytoplasmic tail. This hemITAM phosphorylation induces subsequent downstream signalling leading to calcium mobilisation and platelet activation. Although CLEC-2 stimulation induces powerful platelet activation, the interaction of CLEC-2 with podoplanin is not crucial for haemostasis. During development, CLEC-2 interacts with podoplanin on lymphatic endothelial cells (LECs) and is crucial for blood/lymphatic vessels separation, as well as development of the cerebrovasculature. Moreover, CLEC-2 critically maintains the integrity of high-endothelial venules within lymph nodes post-development through its interaction with podoplanin on fibroblastic reticular cells. Under pathologic conditions, blockade of the CLEC-2/podoplanin interaction has been shown to elicit both detrimental and beneficial effects in a disease-dependent manner. The interaction has been shown to be detrimental in the case of tumour metastasis, HIV propagation and salmonella-mediated liver thrombosis and inflammation. In contrast, upregulation of podoplanin on TH17 cells impairs T-cell expansion and survival in multiple sclerosis and results in enhanced resolution of the disease. This book chapter will discuss the structure and function of the novel platelet receptor CLEC-2 from its discovery to the latest studies carried out on the physiological and pathological role of CLEC-2. This chapter is divided into four sections that cover the identification of CLEC-2 on platelets, the key signalling pathways involved, the role of CLEC-2 in embryonic development and its function in and beyond the vasculature.