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Originally published In Press as doi:10.1074/jbc.M207536200 on September 22, 2002

J. Biol. Chem., Vol. 277, Issue 49, 47572-47580, December 6, 2002
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SHP-2 Is a Dual-specificity Phosphatase Involved in Stat1 Dephosphorylation at Both Tyrosine and Serine Residues in Nuclei*

Tong R. WuDagger , Y. Kate HongDagger , Xu-Dong WangDagger , Mike Y. LingDagger , Ana M. DragoiDagger , Alicia S. ChungDagger , Andrew G. Campbell§, Zhi-Yong HanDagger , Gen-Sheng Feng, and Y. Eugene ChinDagger ||

From the Departments of Dagger  Pathology and Laboratory Medicine and § Molecular Microbiology and Immunology, Brown University School of Medicine, Providence, Rhode Island 02912 and  The Burnham Institute, La Jolla, California 92037

Signal transducer and activator of transcription (STAT) proteins are both tyrosine- and serine-phosphorylated, mediating signal transduction and gene regulation. Following gene regulation, STAT activity in the nucleus is then terminated by a nuclear protein phosphatase(s), which remains unidentified. Using novel antibody arrays to screen the Stat1-specific protein phosphatase(s), we identified a SHP-2-Stat1 interaction in the A431 cell nucleus. SHP-2 and Stat1 nuclear localization and their association in response to either epidermal growth factor or interferon-gamma (IFNgamma ) were confirmed by immunofluorescent staining and affinity precipitation assays. The SHP-2 C-terminal region containing protein-tyrosine phosphatase activity interacted with the C-terminal SH2 transcriptional activation domain of Stat1. In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr701 and the serine residue Ser727 by IFNgamma was enhanced and prolonged. Consistently, purified GST-SHP-2 dephosphorylated Stat1 at both tyrosine and serine residues when immunoprecipitated phospho-Stat1 or a peptide corresponding to the sequence surrounding Tyr(P)701 or Ser(P)727 of Stat1 was used as the substrate. Overexpression of SHP-2 in 293T cells inhibited IFNgamma -dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity. Our findings demonstrate that SHP-2 is a dual-specificity protein phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues and plays an important role in modulating STAT function in gene regulation.

* This work was supported in part by National Institutes of Health Grant RO1 CA82549 (to Y. E. C.).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.

|| To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI 02912. Tel.: 401-863-2540; Fax: 401-863-9008; E-mail: y_eugene_chin@brown.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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