A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis.
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). 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-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.
Scarzello
Anthony J
AJ
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Romero-Weaver
Ana L
AL
Maher
Stephen G
SG
Veenstra
Timothy D
TD
Zhou
Ming
M
Qin
Angel
A
Donnelly
Raymond P
RP
Sheikh
Faruk
F
Gamero
Ana M
AM
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017124:Conserved Sequence; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D018909:src Homology Domains
D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D019000:Phosphotyrosine; D053612:Janus Kinases