The cytoplasmic domains of integrin subunits are involved in bidirectional transmembrane signaling. We report that the cytoplasmic domain of the integrin subunit undergoes limited proteolysis by calpain, an intracellular calcium-dependent protease. Calpain cleavage occurs during platelet aggregation induced by agonists such as thrombin. Five cleavage sites have been identified. Four of these sites (C-terminal to Thr, Tyr, Phe, and Tyr) are utilized in intact platelets and flank two NXXY motifs (Asn-Pro-Leu-Tyr and Asn-Ile-Thr-Tyr). The fifth site (Ala) is accessible to calpain after EDTA treatment of the heterodimer. The NXXY motif is critical to the bidirectional signaling functions of integrins and their association with the cytoskeleton. Thus, calpain cleavage of the cytoplasmic domain may provide a means to regulate integrin signaling functions.

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