Calcium Integrin-binding Protein Activates Platelet Integrin αIIbβ3 *

αIIbβ3, a platelet-specific integrin, plays a critical role in platelet aggregation. The affinity of αIIbβ3 for its ligands such as fibrinogen and von Willebrand factor is tightly regulated in an uncharacterized intracellular process termed inside-out signaling. Calcium integrin-binding protein (CIB) has been identified as a protein interacting with the cytoplasmic tail of the αIIb subunit of αIIbβ3, but its physiological role has not been defined. In the present study, I demonstrate that CIB activates αIIbβ3 bothin vitro and in vivo. CIB interacts directly with the αIIb cytoplasmic tail, thereby increasing the affinity of αIIbβ3 for fibrinogen in anin vitro fibrinogen-binding assay. The interaction of CIB with the αIIb cytoplasmic tail is enhanced in a Ca2+-dependent manner. A physiological agonist, ADP, stimulates platelets, activating αIIbβ3. When the interaction of CIB with the αIIb cytoplasmic tail is blocked in native platelets by a permeable competing peptide, αIIbβ3activation is not detected even in the presence of ADP. This result indicates that direct interaction of CIB with the αIIbcytoplasmic tail converts αIIbβ3 from a resting to an active conformation. This suggests that CIB plays an important role in one of the pathways that modulate the affinity of αIIbβ3 for its ligand.