mechanotransduction.org

http://www.ncbi.nlm.nih.gov – Binding of platelets to fibrinogen via integrin alphaIIbbeta3 stimulates cytoskeletal reorganization and spreading. These responses depend on tyrosine phosphorylation of multiple proteins by Src family members and Syk. Among Src substrates in platelets is ADAP, an adapter with three potential binding partners, SLP-76, VASP and SKAP-HOM. During studies of platelet function under shear flow, we discovered that ADAP(-/-) mouse platelets, unlike ADAP(+/+) platelets, formed unstable rather than stable thrombi in response to carotid artery injury. Moreover, fibrinogen-adherent ADAP(-/-) platelets subjected to shear flow ex vivo showed reduced spreading and smaller zones of contact with the matrix. These abnormalities were not observed under static conditions, and they could not be rescued by stimulating platelets with a PAR4 receptor agonist or by direct alphaIIbbeta activation with MnCl(2), consistent with a defect in outside-in alphaIIbbeta signaling. ADAP(+/+) platelets subjected to shear flow assembled F-actin-rich structures that co-localized with SLP-76 and the Rac1 exchange factor, phospho-Vav1. In contrast, platelets deficient in ADAP, but not those deficient in VASP or SKAP-HOM, failed to form these structures. These results establish that ADAP is an essential component of alphaIIbbeta3-mediated platelet mechanotransduction that promotes F-actin assembly and enables platelet spreading and thrombus stabilization under fluid shear stress. Read »