Platelet receptor proteolysis: GPVI and ADAM10

Glycoprotein VI (GPVI) is a platelet collagen receptor that, together with the von Willebrand factor receptor, GPIb-IX-V, initiates platelet thrombus formation at arterial shear rates. Levels of GPVI also may act as a marker of acute coronary syndrome. GPVI is a member of the immunoreceptor family, and contains two extracellular immunoglobulin domains, a mucin core, a transmembrane domain and a C-terminal cytoplasmic tail. Ligand-induced signaling involves association of calmodulin and Src kinases with the cytoplasmic tail, and co-association with the immunoreceptor tyrosine-based activation motif (ITAM)-bearing Fc receptor γ-chain (FcRγ), that utilizes the Syk kinase pathway. Divergent signaling by GPVI activates integrin α_||bβ₃ that mediates platelet aggregation, and calmodulin-mediated metalloproteinase (ADAM 10)-dependent ectodomain shedding, producing an ∼55-kDa soluble fragment and an ∼ 10-kDa platelet-associated remnant. Current studies are revealing how ADAM10 and GPVI shedding are regulated, with broader implications to the regulation of receptor expression on other cells.