CIB1 is an endogenous inhibitor of agonist-induced integrin αIIbβ3 activation

Abstract

In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of αIIbβ3 is believed to occur in part via engagement of the β3 cytoplasmic tail with talin; however, the role of the αIIb tail and its potential binding partners in regulating αIIbβ3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the αIIb tail, is an endogenous inhibitor of αIIbβ3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced αIIbβ3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to αIIbβ3, thus providing a model for tightly controlled regulation of αIIbβ3 activation.

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

“…An interaction between a IIb CT and talin has been reported (Knezevic et al, 1996;Yuan et al, 2006;Gingras et al, 2009;Raab et al, 2010). Although it might not have a major contribution to a IIb b 3 and talin interaction, a transient and weak interaction between a IIb CT and talin might stabilize the active conformation of a IIb CT during integrin activation.…”

Structure and mechanics of integrin-based cell adhesion

“…An interaction between talin and the αIIb cytoplasmic tail has been described [79], but remains structurally uncharacterized. Further, at least one cytosolic protein, the EF-hand containing calcium and integrin binding protein 1 (CIB1) interacts with hydrophobic residues in the membrane-proximal region of αIIb cytoplasmic tail [80], and interferes with talin binding to an αIIb tail peptide [81], thus potentially acting as a negative regulator of talin-induced integrin activation. The α4-(and α9)-subunits of ligandoccupied integrins also enhance integrin-cytoskeleton links formed under shear force [65], by indirectly binding to talin through the cytoskeleton adaptor paxillin.…”

A Conserved Lipid-binding Loop in the Kindlin FERM F1 Domain Is Required for Kindlin-mediated αIIbβ3 Integrin Coactivation

“…However, integrin binding to extracellular ligands requires a conformational change in the integrin ectodomains, generally termed integrin activation, which results in an increase in affinity for ligand (6,7). Integrin activation and the ensuing cell adhesion and signaling are tightly regulated by intracellular signals that target the cytoplasmic tail of the integrin ␤ subunit (7)(8)(9).…”