The physiological and pathophysiological roles of platelet CLEC-2

Abstract

CLEC-2 is a C-type lectin receptor which is highly expressed on platelets but also found at low levels on different immune cells. CLEC-2 elicits powerful platelet activation upon engagement by its endogenous ligand, the mucin-type glycoprotein podoplanin. Podoplanin is expressed in a variety of tissues, including lymphatic endothelial cells, kidney podocytes, type I lung epithelial cells, lymph node stromal cells and the choroid plexus epithelium. Animal models have shown that the correct separation of the lymphatic and blood vasculatures during embryonic development is dependent on CLEC-2-mediated platelet activation. Additionally, podoplanin-deficient mice show abnormalities in heart, lungs, and lymphoid tissues, whereas absence of CLEC-2 affects brain development. This review summarises the current understanding of the molecular pathways regulating CLEC-2 and podoplanin function and suggests other physiological and pathological processes where this molecular interaction might exert crucial roles.

Figure 1. CLEC-2 mediated platelet signalling

CLEC-2 dimers are cross-linked by podoplanin expressing cells causing clustering of the receptor on the platelet surface. One Syk molecule binds to a pair of CLEC-2 molecules. CLEC-2 phosphorylation and Syk phosphorylation is mediated only partially by Src family kinases (SFK) but largely by Syk itself. Once activated, Syk phosphorylates the downstream LAT signalosome.

Figure 2. Podoplanin-mediated constitutive signalling

Podoplanin interacts with the ezrin/radixin/moesin (ERM) protein family, which provides a structural link to the actin cytoskeleton, and promotes RhoA activation and cell migration in the absence of a ligand. Podoplanin expression also induces epithelial to mesenchymal transition in different cell types.