CALPAIN CLEAVAGE OF THE CYTOPLASMIC DOMAIN OF THE INTEGRIN BETA(3) SUBUNIT

The cytoplasmic domains of integrin beta subunits are involved in bidi rectional transmembrane signaling. We report that the cytoplasmic doma in of the integrin beta(3) subunit undergoes limited proteolysis by ca lpain, an intracellular calcium-dependent protease, Calpain cleavage o ccurs during platelet aggregation induced by agonists such as thrombin . Five cleavage sites have been identified. Four of these sites (C-ter minal to Thr(741), Tyr(747), Phe(754) and Tyr(759)) are utilized in in tact platelets and flank two NXXY motifs (Asn(744)-Pro-Leu-Tyr(747) an d Asn(756)-Ile-Thr-Tyr(759)). The fifth site (Ala(735)) is accessible to calpain after EDTA treatment of the alpha(IIb)beta(3) heterodimer, The NXXY motifis critical to the bidirectional signaling functions of beta(3) integrins and their association with the cytoskeleton. Thus, c alpain cleavage of the beta(3) cytoplasmic domain may provide a means to regulate integrin signaling functions.