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Cutting Edge: Selective Tyrosine Dephosphorylation of Interferon-Activated Nuclear STAT5 by the VHR Phosphatase¹

Richard Hoyt^2,*, Wei Zhu^2,*, Fabio Cerignoli^2,, Andres Alonso, Tomas Mustelin and Michael David^3,*

^* Division of Biological Sciences and University of California Cancer Center, University of California La Jolla, CA 92093 and The Burnham Institute, La Jolla, CA 92037

Cytokine-induced tyrosine phosphorylation of the transcription factor STAT5 is required for its transcriptional activity. In this article we show that the small dual-specificity phosphatase VHR selectively dephosphorylates IFN-- and -activated, tyrosine-phosphorylated STAT5, leading to the subsequent inhibition of STAT5 function. Phosphorylation of VHR at Tyr¹³⁸ was required for its phosphatase activity toward STAT5. In addition, the Src homology 2 domain of STAT5 was required for the effective dephosphorylation of STAT5 by VHR. The tyrosine kinase Tyk2, which mediates the phosphorylation of STAT5, was also responsible for the phosphorylation of VHR at Tyr¹³⁸.

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.

¹ This work was supported in part by National Institutes of Health Grant R01 CA80105 (to M. D.).

² R.H., W.Z, and F. C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Michael David, University of California Department of Biology, Bonner Hall 3138, 9500 Gilman Drive, La Jolla, CA 92093-0322. E-mail address: midavid{at}ucsd.edu

⁴ Abbreviations used in this paper: TcPTP, T cell protein tyrosine phosphatase; HA, hemagglutinin; PTP, protein tyrosine phosphatase; SH2, Src homology 2; Tyk2, tyrosine kinase 2; WT, wild type.