Actin polymerization regulates glycoprotein Ib alpha shedding

Glycoprotein (GP) Ib alpha shedding mediated by ADAM17 (a disintegrin and metalloproteinase 17) plays an important role in negatively regulating platelet function and thrombus formation. However, the mechanism of GPIb alpha shedding remains elusive. Here, we show that jasplakinolide (an actin-polymerizing peptide)-induced actin polymerization results in GPIb alpha shedding and impairs platelet function. Thrombin and A23187-induced GPIb alpha shedding is increased by jasplakinolide; in contrast, GPIb alpha shedding is reduced by a depolymerization regent (cytochalasin B). We find that actin polymerization activates calpain leading to filamin A hydrolyzation. We further demonstrate that the interaction of filamin A with the cytoplasmic domain of GPIb alpha plays a critical role in regulating actin polymerization-induced GPIb alpha shedding. Taken together, these data demonstrate that actin polymerization regulates ADAM17-mediated GPIb alpha shedding, suggesting a novel strategy to negatively regulate platelet function.