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Vol. 18, Issue 7, 2455-2462, July 2007

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A Mutation in the SH2 Domain of STAT2 Prolongs Tyrosine Phosphorylation of STAT1 and Promotes Type I IFN-induced Apoptosis

Anthony J. Scarzello^*, Ana L. Romero-Weaver^*, Stephen G. Maher^*, Timothy D. Veenstra, Ming Zhou, Angel Qin^*, Raymond P. Donnelly, Faruk Sheikh, and Ana M. Gamero^*

*Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702; and Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

Submitted September 21, 2006; Revised April 4, 2007; Accepted April 11, 2007
Monitoring Editor: William Tansey

Type I interferons (IFN-/) induce apoptosis in certain tumor cell lines but not others. Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN- stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN- could account for one difference between tumor cell lines that undergo IFN-–induced apoptosis compared with those that display an antiproliferative response but do not die.

The publisher or recipient acknowledges the right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Address correspondence to: A. M. Gamero (gameroa{at}ncifcrf.gov)

Abbreviations used: GRR, gamma responsive region; IFN, interferon; ISGF3, interferon-stimulated gene factor 3; ISRE, interferon-stimulated responsive element; SH2, Src-homology-2; STAT, signal transducers and activators of transcription; TcPTP, T-cell protein tyrosine phosphatase.