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J. Biol. Chem., Vol. 279, Issue 21, 22571-22577, May 21, 2004

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A Shear-restricted Pathway of Platelet Procoagulant Activity Is Regulated by IQGAP1^*

Wadie F. Bahou¶, Lesley Scudder, David Rubenstein||, and Jolyon Jesty

From the Department of Medicine, ^||Department of Biomedical Engineering, and Program in Genetics, State University of New York at Stony Brook, Stony Brook, New York 11794-8151

Circulating blood platelets regulate the initial phase of the hemostatic response through adhesive and aggregatory events and by providing the necessary procoagulant surface for prothrombinase complex assembly and thrombin generation. The signaling pathway(s) that regulate platelet procoagulant activity are largely unknown, although they are distinct from platelet aggregatory signals linked to fibrinogen ligation to the conformationally active _IIB3 integrin. We describe a novel intracellular signaling mechanism involving platelet IQGAP1 that specifically regulates the development of platelet procoagulant activity under conditions of mechanical shear stress. Murine platelets that are deficient in IQGAP1 demonstrate increased prothrombinase activity compared with wild-type littermate controls when activated by a physiological shear stress of 16 dynes/cm² (shear rates of 1600 s^-1) (p < 0.0001), corresponding to 2.5 times the normal shear stress, or 40% degree of stenosis in coronary arteries. The exaggerated prothrombinase activity is not associated with enhanced platelet microvesiculation (cytoskeletal proteolysis) and occurs independently of the intracellular calcium release, [Ca²⁺]_i, but it is specifically coupled to the -granule exocytic pathway without concomitant effects on aminophospholipid exposure. These observations identify platelet IQGAP1 as an important modulator of normal hemostasis and as an appropriate pharmacological target for control of platelet procoagulant function.

Received for publication, March 8, 2004 , and in revised form, March 15, 2004.

^* This work was supported by Grants HL49141 and HL53665 National Institutes of Health and a Veterans Affairs Research Enhancement Award Program award (to W. F. B.) and Center Grant M01 10710-5 N.I.H. to the University Hospital General Clinical Research Center. The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Division of Hematology, Health Sciences Center T15-040, State University of New York, Stony Brook, NY 11794-8151. Tel.: 631-444-2059; Fax: 631-444-7530; E-mail: wbahou{at}notes.cc.sunysb.edu.

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