title: Calpain cleavage of the cytoplasmic domain of the integrin beta 3 subunit.
abstract: The cytoplasmic domains of integrin beta subunits are involved in bidirectional transmembrane signaling. We report that the cytoplasmic domain of the integrin beta 3 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 Thr741, Tyr747, Phe754, and Tyr759) are utilized in intact platelets and flank two NXXY motifs (Asn744-Pro-Leu-Tyr747 and Asn756-Ile-Thr-Tyr759). The fifth site (Ala735) is accessible to calpain after EDTA treatment of the alpha IIb beta 3 heterodimer. The NXXY motif is critical to the bidirectional signaling functions of beta 3 integrins and their association with the cytoskeleton. Thus, calpain cleavage of the beta 3 cytoplasmic domain may provide a means to regulate integrin signaling functions.
authors.affiliation: Department of Vascular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.forename: T C
authors.initials: TC
authors.lastname: Saido
authors.forename: S
authors.initials: S
authors.lastname: Tsubuki
authors.forename: F E
authors.initials: FE
authors.lastname: Indig
authors.forename: M J
authors.initials: MJ
authors.lastname: Williams
authors.forename: M H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000302:isolation & purification / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D003593:Cytoplasm; D006801:Humans; D039661:Integrin beta3; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000302:isolation & purification / Q000378:metabolism*; D011817:Rabbits; D013379:Substrate Specificity; D013917:Thrombin / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D039661:Integrin beta3; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin; D002154:Calpain