Pharmaceutical Sciences Faculty Publications

A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis.

Document Type

Article

Publication Date

7-1-2007

Journal Title

Molecular Biology of the Cell

ISSN

1059-1524

Volume

18

Issue

7

First Page

2455

Last Page

2462

DOI

10.1091/mbc.e06-09-0843

PubMed ID

17442890

PubMed Central® ID

PMC1924825

Abstract

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.

Keywords

Amino acid motifs, apoptosis, cell line, tumor, cell nucleus, conserved sequence, interferon type I, janus kinases, mutation, phosphorylation, phosphotyrosine, transcription, genetic

Link to Full Text

Share

COinS