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J. Biol. Chem., Vol. 279, Issue 31, 32196-32204, July 30, 2004

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SHIP1 and Lyn Kinase Negatively Regulate Integrin _IIb3 Signaling in Platelets^*

Mhairi J. Maxwell, Yuping Yuan, Karen E. Anderson, Margaret L. Hibbs¶, Hatem H. Salem, and Shaun P. Jackson||

From the Australian Centre for Blood Diseases, Department of Medicine, Monash University, Box Hill Hospital, Victoria 3128, Australia and the ^¶Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Post Office Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia

Integrin _IIb3 plays a critical role in platelet function, promoting a broad range of functional responses including platelet adhesion, spreading, aggregation, clot retraction, and platelet procoagulant function. Signaling events operating downstream of this receptor (outside-in signaling) are important for these responses; however the mechanisms negatively regulating integrin _IIb3 signaling remain ill-defined. We demonstrate here a major role for the Src homology 2 domain-containing inositol 5-phosphatase (SHIP1) and Src family kinase, Lyn, in this process. Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin _IIb3-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃) accumulation, necessary for a cytosolic calcium response and platelet spreading. SHIP1 phosphorylation and PtdIns(3,4,5)P₃ metabolism is partially regulated through Lyn kinase, resulting in an enhanced calcium flux and spreading response in Lyn-deficient mouse platelets. Analysis of platelet adhesion dynamics under physiological blood flow conditions revealed an important role for SHIP1 in regulating platelet adhesion on fibrinogen. Specifically, SHIP1-dependent PtdIns(3,4,5)P₃ metabolism down-regulates the stability of integrin _IIb3-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts. These studies define a major role for SHIP1 and Lyn as negative regulators of integrin _IIb3 adhesive and signaling function.

Received for publication, January 23, 2004 , and in revised form, April 19, 2004.

^* This work was supported in part by grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Australian Centre for Blood Diseases, Dept. of Medicine, Monash University, Box Hill Hospital, Victoria 3128, Australia. Tel.: 61-3-98950311; Fax: 61-3-98950332; E-mail: Shaun.Jackson{at}med.monash.edu.au.

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