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J. Biol. Chem., Vol. 282, Issue 39, 28648-28658, September 28, 2007

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Identification of a Unique Co-operative Phosphoinositide 3-Kinase Signaling Mechanism Regulating Integrin _IIb3 Adhesive Function in Platelets^*

Simone M. Schoenwaelder, Akiko Ono, Sharelle Sturgeon, Siew Mei Chan, Pierre Mangin, Mhairi J. Maxwell, Shannon Turnbull, Megha Mulchandani, Karen Anderson, Gilles Kauffenstein, Gordon W. Rewcastle, Jackie Kendall, Christian Gachet^¶, Hatem H. Salem, and Shaun P. Jackson¹

From the Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia 3004, ^¶INSERM U.311, EFS-Alsace, Strasbourg, France, and the Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1020, New Zealand

Phosphoinositide (PI) 3-kinases play an important role in regulating the adhesive function of a variety of cell types through affinity modulation of integrins. Two type I PI 3-kinase isoforms (p110 and p110) have been implicated in G_i-dependent integrin _IIb3 regulation in platelets, however, the mechanisms by which they coordinate their signaling function remains unknown. By employing isoform-selective PI 3-kinase inhibitors and knock-out mouse models we have identified a unique mechanism of PI 3-kinase signaling co-operativity in platelets. We demonstrate that p110 is primarily responsible for G_i-dependent phosphatidylinositol 3,4-bisphosphate (PI(3,4)P₂) production in ADP-stimulated platelets and is linked to the activation of Rap1b and AKT. In contrast, defective integrin _IIb3 activation in p110^-/- platelets was not associated with alterations in the levels of PI(3,4)P₂ or active Rap1b/AKT. Analysis of the effects of active site pharmacological inhibitors confirmed that p110 principally regulated integrin _IIb3 activation through a non-catalytic signaling mechanism. Inhibition of the kinase function of PI 3-kinases, combined with deletion of p110, led to a major reduction in integrin _IIb3 activation, resulting in a profound defect in platelet aggregation, hemostatic plug formation, and arterial thrombosis. These studies demonstrate a kinase-independent signaling function for p110 in platelets. Moreover, they demonstrate that the combined catalytic and non-catalytic signaling function of p110 and p110 is critical for P2Y₁₂/G_i-dependent integrin_IIb3 regulation. These findings have potentially important implications for the rationale design of novel antiplatelet therapies targeting PI 3-kinase signaling pathways.

Received for publication, May 29, 2007 , and in revised form, August 2, 2007.

^* This work was supported by grants from the National Heart Foundation of Australia and the National Health and Medical Research Council of Australia, in addition to Association de Recherche et de Développment en médicine et Sante Publique (France). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and video.

¹ To whom correspondence should be addressed. Tel.: 613-9903-0122; Fax: 613-9903-0228; E-mail: Shaun.Jackson{at}med.monash.edu.au.

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