Role for ADAP in shear flow-induced platelet mechanotransduction

摘要: Binding of platelets to fibrinogen via integrin alphaIIbbeta3 stimulates cytoskeletal reorganization and spreading. These responses depend on tyrosine phosphorylation multiple proteins by Src family members Syk. Among substrates in is adhesion- degranulation-promoting adapter protein (ADAP), an with potential binding partners: SLP-76, VASP, SKAP-HOM. During studies platelet function under shear flow, we discovered that ADAP(-/-) mouse platelets, unlike ADAP+/+ formed unstable thrombi response carotid artery injury. Moreover, fibrinogen-adherent flow ex vivo showed reduced spreading smaller zones contact the matrix. abnormalities were not observed static conditions, they could be rescued stimulating a PAR4 receptor agonist or direct activation MnCl2, consistent defect outside-in signaling. subjected assembled F-actin-rich structures colocalized SLP-76 Rac1 exchange factor, phospho-Vav1. In contrast, deficient ADAP, but those VASP SKAP-HOM, failed form these structures. results establish ADAP essential component alphaIIbbeta3-mediated mechanotransduction promotes F-actin assembly enables thrombus stabilization fluid stress.