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MBC in Press, published online ahead of print April 18, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0843

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Submitted on September 21, 2006
Revised on April 4, 2007
Accepted on April 11, 2007

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,{dagger} Ming Zhou,{dagger} Angel Qin,* Raymond P. Donnelly,{ddagger} Faruk Sheikh,{ddagger} 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; {dagger}Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702; {ddagger}Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

Monitoring Editor: William Tansey

Type I interferons (IFN-{alpha}/{beta}) 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). While 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 following IFN{alpha} stimulation compared with wild type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-{alpha} could account for one difference between tumor cell lines that undergo IFN-{alpha} induced apoptosis compared with those that display an antiproliferative response but do not die.

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






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