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The eIF2α kinase PKR is a negative regulator of Stat1 and Stat3
Author(s) -
Raven Jennifer Frances,
Wang Shuo,
Kazemi Shirin,
Baltzis Dionissois,
Hatzoglou Maria,
Tremblay Michel L.,
Koromilas Antonis E.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a496-c
Subject(s) - protein kinase r , regulator , kinase , microbiology and biotechnology , chemistry , biology , protein kinase a , mitogen activated protein kinase kinase , biochemistry , gene
Cancerous cells contain overactive proteins, including the transcription factor Stat1, which is hyperphosphorylated in various blood and head and neck cancers. Numerous mechanisms exist which regulate Stat1, including dephosphorylation in the nucleus by the tyrosine phosphatase TC‐PTP. Stat1 activity is further controlled by the eIF2α kinase PKR, which inhibits the formation of Stat1 transcriptional complexes. We set out to determine if an indirect pathway exists that controls Stat1 phosphorylation via PKR. Using an inducible PKR cell line, we demonstrated that tyrosine phosphorylation of Stat1, and a related family member Stat3, is reduced in the presence of active PKR. Targeted reduction of TC‐PTP by RNAi in the same cell line resulted in a partial rescue of Stat1 and Stat3 phosphorylation, transcriptional activity and nuclear localization. PKR exerts this regulation by phosphorylating both TC‐PTP and eIF2α, thus controlling translation. These results describe a previously unknown pathway regulating the activity of Stat1 and Stat3, and also identify a TC‐PTP as a novel substrate of PKR. Since both PKR and Stat1 have anti‐tumour activity, and Stat3 is a proto‐oncogene, further insight into the relationship between these proteins may allow us to comprehend their roles in cancer development and progression. This project was funded by a grant from the CIHR/CBCRA.