MECHANISMS OF SIGNAL TRANSDUCTION
Identification of Shp-2 as a Stat5A Phosphatase*

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Stat5A, a member of the signal transducers and activators of transcription (Stat) family, is activated upon a single tyrosine phosphorylation. Although much is known about the activation process, the mechanism by which the tyrosine-phosphorylated Stat5A proteins are inactivated is largely unknown. In this report, we demonstrate that down-regulation of the tyrosine-phosphorylated Stat5A was via dephosphorylation. Using tyrosine-phosphorylated peptides derived from Stat5A, we were able to purify protein-tyrosine phosphatase Shp-2 from cell lysates. Shp-2, but not Shp-1, specifically interacted with Stat5A in vivo, and the interaction was tyrosine phosphorylation-dependent. Moreover, Shp-2 was able to accelerate Stat5A dephosphorylation, and dephosphorylation of Stat5A was dramatically delayed in Shp-2-deficient cells. Therefore, we conclude that Shp-2 is a Stat5A phosphatase, which down-regulates the active Stat5A in vivo.

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Published, JBC Papers in Press, March 3, 2003, DOI 10.1074/jbc.M210572200

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This work was supported by funds from the Blood Research Institute Foundation of the Blood Center of Southeastern Wisconsin (to R. W. and D. W.) and National Institutes of Health Grant RO1 AI52327-01 (to R. W.) and RO1 HL073284 (to D. W.), partially supported by National Institutes of Health Grants 1R01CA79891 and 1R01GM58893 (to T. Y.), and Grant R01GM53660 and RO1 CA78606 (to G. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.