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J. Biol. Chem., Vol. 279, Issue 53, 55089-55096, December 31, 2004

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SHIP Family Inositol Phosphatases Interact with and Negatively Regulate the Tec Tyrosine Kinase^*

Michael G. Tomlinson¶, Victoria L. Heath||, Chris W. Turck**, Steve P. Watson, and Arthur Weiss

From the Department of Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California 94143 and the Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom

The Tec family of protein-tyrosine kinases (PTKs), that includes Tec, Itk, Btk, Bmx, and Txk, plays an essential role in phospholipase C (PLC) activation following antigen receptor stimulation. This function requires activation of phosphatidylinositol 3-kinase (PI 3-kinase), which promotes Tec membrane localization through phosphatidylinositol 3,4,5-trisphosphate (PtdIns 3,4,5-P₃) generation. The mechanism of negative regulation of Tec family PTKs is poorly understood. In this study, we show that the inositol 5' phosphatases SHIP1 and SHIP2 interact preferentially with Tec, compared with other Tec family members. Four lines of evidence suggest that SHIP phosphatases are negative regulators of Tec. First, SHIP1 and SHIP2 are potent inhibitors of Tec activity. Second, inactivation of the Tec SH3 domain, which is necessary and sufficient for SHIP binding, generates a hyperactive form of Tec. Third, SHIP1 inhibits Tec membrane localization. Finally, constitutively targeting Tec to the membrane relieves SHIP1-mediated inhibition. These data suggest that SHIP phosphatases can interact with and functionally inactivate Tec by de-phosphorylation of local PtdIns 3,4,5-P₃ and inhibition of Tec membrane localization.

Received for publication, July 19, 2004 , and in revised form, October 12, 2004.

^* This work was supported, in part, by the Rosalind Russell Medical Research Center for Arthritis and by Grant CA72531 from the NCI, National Institutes of Health. 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.

^|| Current address: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.

^** Current address: Max Planck Institute of Psychiatry, Munich, Germany.

^¶ To whom correspondence should be addressed: Centre for Cardiovascular Sciences, Division of Medical Sciences, Institute of Biomedical Research, Wolfson Drive, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Tel.: 0121-414-8308; Fax: 0121-415-8817; E-mail: m.g.tomlinson{at}bham.ac.uk.

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