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Published 17 January 2006. doi:10.1083/jcb.200505131
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 2, 169-175
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Report

 CIB1 is an endogenous inhibitor of agonist-induced integrin {alpha}IIbß3 activation

Weiping Yuan1, Tina M. Leisner1, Andrew W. McFadden1, Zhengyan Wang1,2, Mark K. Larson1, Shantres Clark1, Christel Boudignon-Proudhon1, Stephen C.-T. Lam5, and Leslie V. Parise1,3,4

1 Department of Pharmacology, 2 Dental Research Center, 3 Carolina Cardiovascular Biology Center, and 4 Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599
5 Department of Pharmacology, University of Illinois, Chicago, IL 60680

Correspondence to Leslie V. Parise: parise{at}med.unc.edu


Abstract
In response to agonist stimulation, the {alpha}IIbß3 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 {alpha}IIbß3 is believed to occur in part via engagement of the ß3 cytoplasmic tail with talin; however, the role of the {alpha}IIb tail and its potential binding partners in regulating {alpha}IIbß3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the {alpha}IIb tail, is an endogenous inhibitor of {alpha}IIbß3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced {alpha}IIbß3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to {alpha}IIbß3, thus providing a model for tightly controlled regulation of {alpha}IIbß3 activation.

W. Yuan and T.M. Leisner contributed equally to this paper.

M.K. Larson's present address is Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK.

Abbreviations used in this paper: CIB1, calcium and integrin binding protein 1; pAb, polyclonal antibody; PAK1, p21-activated kinase 1; PAR4P, protease-activated receptor 4 activating peptide; siRNA, small interfering RNA; THD, talin head domain.


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