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

EMBO J. 2001 May 15;20(10):2487-96. doi: 10.1093/emboj/20.10.2487.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-fos
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Tyrosine
  • Serine
  • Receptors, Platelet-Derived Growth Factor
  • eIF-2 Kinase
  • Mitogen-Activated Protein Kinases