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Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3.

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 2alpha (eIF-2alpha). 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.

Pubmed ID: 11350938

Authors

  • Deb A
  • Zamanian-Daryoush M
  • Xu Z
  • Kadereit S
  • Williams BR

Journal

The EMBO journal

Publication Data

May 15, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: P01-CA62220
  • Agency: NIAID NIH HHS, Id: R01-AI34039

Mesh Terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins
  • Enzyme Activation
  • Gene Expression
  • Mice
  • Mitogen-Activated Protein Kinases
  • Phosphorylation
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-fos
  • Receptors, Platelet-Derived Growth Factor
  • STAT3 Transcription Factor
  • Serine
  • Signal Transduction
  • Trans-Activators
  • Tyrosine
  • eIF-2 Kinase