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The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in

Xuerui Yang1, Aritro Nath, Michael J Opperman

  • 1Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA.

Molecular Biology of the Cell
|August 6, 2010
PubMed

Insights

The double-stranded RNA-dependent protein kinase (PKR) regulates insulin signaling pathways. This study reveals PKR

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Virology

Background:

  • The double-stranded RNA-dependent protein kinase (PKR) is known for its role in antiviral defense by inhibiting protein translation.
  • Insulin signaling is crucial for glucose homeostasis and energy metabolism, involving key mediators like Insulin Receptor Substrates (IRS).
  • Previous research indicated that insulin down-regulates PKR phosphorylation.

Purpose of the Study:

  • To investigate the novel function of PKR in regulating IRS proteins.
  • To elucidate the mechanisms by which PKR affects IRS1 and IRS2.
  • To understand the interplay between PKR and insulin signaling pathways.

Main Methods:

  • Investigated the effect of PKR on IRS1 and IRS2 phosphorylation and transcription.
  • Utilized protein kinase assays to identify mediating kinases (JNK, IKK) for IRS1 regulation.
  • Employed transcription factor analysis to understand IRS2 regulation by PKR via FoxO1.

Main Results:

  • PKR up-regulates inhibitory phosphorylation of IRS1 at Ser312, suppressing its tyrosine phosphorylation, mediated by JNK and IKK.
  • PKR regulates IRS2 transcription, not post-translational modification, through the transcription factor FoxO1.
  • Demonstrated distinct mechanisms of IRS1 and IRS2 regulation by PKR.

Conclusions:

  • PKR, traditionally known for antiviral responses, plays a novel role in regulating key components of insulin signaling, IRS1 and IRS2.
  • PKR influences insulin signaling through both post-translational modification of IRS1 and transcriptional regulation of IRS2.
  • These findings reveal a new link between viral response pathways and metabolic regulation via PKR and IRS proteins.

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