Journal
EMBO JOURNAL
Volume 20, Issue 10, Pages 2487-2496Publisher
WILEY
DOI: 10.1093/emboj/20.10.2487
Keywords
c-fos induction; ERK activation; PDGF; PKR; Stat3 phosphorylation
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Funding
- NCI NIH HHS [P01 CA062220, P01-CA62220] Funding Source: Medline
- NIAID NIH HHS [R01 AI034039, R01-AI34039] Funding Source: Medline
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The double-stranded RNA (dsRNA)-activated protein kinase PKR is an interferon (IFN)-induced enzyme that controls protein synthesis through phosphorylation of eukaryotic initiation factor 2 alpha (eIF-2 alpha), PKR also regulates signals initiated by diverse stimuli, including dsRNA, IFN-gamma tumor necrosis factor-alpha, interleukin-1 and lipopolysaccharide, to different transcription factors, resulting in pro-inflammatory gene expression. Stat3 plays an essential role in promoting cell survival and proliferation by different growth factors, including platelet-derived growth factor (PDGF), Here we show that PKR physically interacts with Stat3 and is required for PDGF-induced phosphorylation of Stat3 at Tyr705 and Ser727, resulting in DNA binding and transcriptional activation. PKR-mediated phosphorylation of Stat3 on Ser727 is indirect and channeled through Erks, Although PKR is pre-associated with the PDGF beta -receptor, treatment with PDGF only modestly activates PKR, However, the induction of c-fos by PDGF is defective in PKR-null cells. Taken together, these results establish PKR as an upstream regulator of activation of Stat3 and as a common mediator of both growth-promoting and growth-inhibitory signals.
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