Platelet Membrane Receptor Proteolysis: Implications for Platelet Function

Abstract

The activities of adhesion and signaling receptors in platelets are controlled by several mechanisms. An important way of regulation is provided by proteolytic cleavage of several of these receptors, leading to either a gain or a loss of platelet function. The proteases involved are of different origins and types: (i) present as precursor in plasma, (ii) secreted into the plasma by activated platelets or other blood cells, or (iii) intracellularly activated and cleaving cytosolic receptor domains. We provide a comprehensive overview of the proteases acting on the platelet membrane. We describe how these are activated, which are their target proteins, and how their proteolytic activity modulates platelet functions. The review focuses on coagulation-related proteases, plasmin, matrix metalloproteinases, ADAM(TS) isoforms, cathepsins, caspases, and calpains. We also describe how the proteolytic activities are determined by different platelet populations in a thrombus and conversely how proteolysis contributes to the formation of such populations.

Keywords: ADAM; MMP; calpain; caspase; coagulation factors; platelets; receptor proteolysis.

Figure 1

Coagulation-induced receptor proteolysis. Proteolytic activation mechanism of coagulation factors at the platelet membrane, progressing to thrombin-induced activation of proteolytic-activated receptor (PAR) isoforms and shedding of glycoprotein V (GPV) and GPVI with a schematic overview of proteolytic cleavage sites.

Figure 2

Matrix metalloproteinase (MMP)-1/2 induced platelet activation. Overview of mechanisms resulting in MMP-1/2 induced or enhanced platelet activation.

Figure 3

ADAM10- and ADAM 17-mediated proteolysis of platelet receptors. Illustration of ADAM10-mediated receptor shedding of glycoprotein V (GPV) and ADAM17-mediated receptor shedding of GPIbα with proteolytic cleavage sites indicated.

Figure 4

Inactivation of integrin β₃ chain by intracellular proteolysis. Intracellular proteolysis mediated by calpains upon prolonged Ca²⁺ rise or by caspases during apoptosis leads to cleavage of the integrin β₃ chain, next to cytoskeletal-linked signal proteins.