Calcium integrin-binding protein activates platelet integrin alpha IIbbeta 3.
alpha(IIb)beta(3), a platelet-specific integrin, plays a critical role in platelet aggregation. The affinity of alpha(IIb)beta(3) 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 alpha(IIb) subunit of alpha(IIb)beta(3), but its physiological role has not been defined. In the present study, I demonstrate that CIB activates alpha(IIb)beta(3) both in vitro and in vivo. CIB interacts directly with the alpha(IIb) cytoplasmic tail, thereby increasing the affinity of alpha(IIb)beta(3) for fibrinogen in an in vitro fibrinogen-binding assay. The interaction of CIB with the alpha(IIb) cytoplasmic tail is enhanced in a Ca(2+)-dependent manner. A physiological agonist, ADP, stimulates platelets, activating alpha(IIb)beta(3). When the interaction of CIB with the alpha(IIb) cytoplasmic tail is blocked in native platelets by a permeable competing peptide, alpha(IIb)beta(3) activation is not detected even in the presence of ADP. This result indicates that direct interaction of CIB with the alpha(IIb) cytoplasmic tail converts alpha(IIb)beta(3) 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 alpha(IIb)beta(3) for its ligand.
Tsuboi
Shigeru
S
Glycobiology Program, Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA. stsuboi@burnham.org
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding
D008565:Membrane Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D002118:Calcium