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Originally published In Press as doi:10.1074/jbc.M108727200 on January 25, 2002

J. Biol. Chem., Vol. 277, Issue 14, 11949-11956, April 5, 2002
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Lateral Clustering of Platelet GP Ib-IX Complexes Leads to Up-regulation of the Adhesive Function of Integrin alpha IIbbeta 3*

Ana Kasirer-FriedeDagger , Jerry Ware§, Lijun LengDagger , Patrizia Marchese§, Zaverio M. Ruggeri§, and Sanford J. ShattilDagger §

From the Departments of Dagger  Cell Biology and § Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Binding of von Willebrand factor (VWF) to GP Ib-IX mediates initial platelet adhesion and increases the subsequent adhesive function of alpha IIbbeta 3. Because these responses are promoted most effectively by large VWF multimers, we hypothesized that receptor clustering modulates GP Ib-IX function. To test this, GP IX was fused at its cytoplasmic tail to tandem repeats of FKBP, and GP Ib-IX(FKBP)2 and alpha IIbbeta 3 were expressed in Chinese hamster ovary cells. Under flow conditions at wall shear rates of up to 2000 s-1, GP Ib-IX(FKBP)2 mediated cell tethering to immobilized VWF, just as in platelets. Conditional oligomerization of GP Ib-IX(FKBP)2 by AP20187, a cell-permeable FKBP dimerizer, caused a decrease in cell translocation velocities on VWF (p < 0.001). Moreover, clustering of GP Ib-IX(FKBP)2 by AP20187 led to an increase in alpha IIbbeta 3 function, manifested under static conditions by increased cell adhesion to fibrinogen (p < 0.01) and under flow by increased stable cell adhesion to VWF (p < 0.04). Clustering of GP Ib-IX(FKBP)2 also stimulated rapid tyrosine phosphorylation of ectopically expressed Syk, a putative downstream effector of GP Ib-IX in platelets. These studies establish that GP Ib-IX oligomerization, per se, affects the interaction of this receptor with VWF and its ability to influence the adhesive function of alpha IIbbeta 3. By extrapolation, GP Ib-IX clustering in platelets may promote thrombus formation.

* This work was supported by National Institutes of Health Grants HL 56595 and HL 42846. This work was presented in part at the XVIIIth Congress of the International Society on Thrombosis and Hemostasis, Paris, France, July 2001 and published in abstract form (A. K.-F., J. W., L. L., Z. M. R., and S. J. S. (2001) Thromb. Hemostasis 86, OC1688).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., VB-5, La Jolla, CA 92037. Tel.: 858-784-7148; Fax: 858-784-7422; E-mail: shattil@scripps.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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