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J. Biol. Chem., Vol. 279, Issue 39, 40475-40483, September 24, 2004

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Regulation of SHP-1 Tyrosine Phosphatase in Human Platelets by Serine Phosphorylation at Its C Terminus^*

Matthew L. Jones, Johnathan D. Craik, Jonathan M. Gibbins, and Alastair W. Poole¶

From the Department of Pharmacology, School of Medical Sciences, University Walk, Bristol BS8 1TD and School of Animal and Microbial Sciences, University of Reading, Whitenights, Reading RG6 6AJ, United Kingdom

SHP-1 is a Src homology 2 (SH2) domain-containing tyrosine phosphatase that plays an essential role in negative regulation of immune cell activity. We describe here a new model for regulation of SHP-1 involving phosphorylation of its C-terminal Ser⁵⁹¹ by associated protein kinase C. In human platelets, SHP-1 was found to constitutively associate with its substrate Vav1 and, through its SH2 domains, with protein kinase C. Upon activation of either PAR1 or PAR4 thrombin receptors, the association between the three proteins was retained, and Vav1 became phosphorylated on tyrosine and SHP-1 became phosphorylated on Ser⁵⁹¹. Phosphorylation of SHP-1 was mediated by protein kinase C and negatively regulated the activity of SHP-1 as demonstrated by a decrease in the in vitro ability of SHP-1 to dephosphorylate Vav1 on tyrosine. Protein kinase C therefore critically and negatively regulates SHP-1 function, forming part of a mechanism to retain SHP-1 in a basal active state through interaction with its SH2 domains, and phosphorylating its C-terminal Ser⁵⁹¹ upon cellular activation leading to inhibition of SHP-1 activity and an increase in the tyrosine phosphorylation status of its substrates.

Received for publication, March 17, 2004 , and in revised form, July 14, 2004.

^* The work was supported by Project Grants 064785 and 069572 (to A. W. P.) from the Wellcome Trust and the British Heart Foundation Grant PG/2000087. 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: Dept. of Pharmacology, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK. Tel.: 44-117-928-7635; Fax: 44-117-925-0168; E-mail: a.poole{at}bris.ac.uk.

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