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Integrin mechanotransduction is a ubiquitous biological process. Mechanical forces are transduced transmembranously by an integrin's ligand-bound extracellular domain through its β-subunit's cytoplasmic domain connected to the cytoskeleton. This often culminates in the activation of tyrosine kinases directing cell responses. The delicate balance between hemostasis and thrombosis requires exquisitely fine-tuned integrin function, and balance is maintained in vivo despite that the major platelet integrin α11bβ3 is continuously subjected to frictional or shearing forces generated by laminar blood flow. To test the hypothesis that platelet function is regulated by the direct effects of mechanical forces on α11bβ3, we examined α11bβ3/cytoskeletal interactions in human platelets exposed to shear stress in a cone-plate viscometer. We observed that α-actinin, myosin heavy chain, and Syk coimmunoprecipitate with α11bβ3 in resting platelets and that 120 dyn/cm² shear stress leads to their disassociation from α11bβ3. Shear-induced disassociation of α-actinin and myosin heavy chain from the 33 tail is unaffected by blocking von Willebrand factor (VWF) binding to glycoprotein (Gp) GpIb-IX-V but abolished by blocking VWF binding to α11bβ3. Syk's disassociation from β3 is inhibited when VWF binding to either GpIb-IX-V or α11bβ3 is blocked. Shear stress-induced phosphorylation of SLP-76 and its association with tyrosine-phosphorylated adhesion and degranulation-promoting adapter protein are inhibited by blocking ligand binding to α11bβ3 but not by blocking ligand binding to GpIb-IX-V. Chinese hamster ovary cells expressing α11bβ3 with β3 truncated of its cytoskeletal binding domains demonstrate diminished shear-dependent adhesion and cohesion. These results support the hypothesis that shear stress directly modulates α11bβ3 function and suggest that shear-induced α11bβ3-mediated signaling contributes to the regulation of platelet aggregation by directing the release of constraining cytoskeletal elements from the β3-tail. [ABSTRACT FROM AUTHOR]