Insulin treatment promotes tyrosine phosphorylation of PKR and inhibits polyIC induced PKR threonine phosphorylation

Insulin treatment promotes tyrosine phosphorylation of PKR and inhibits polyIC induced PKR... Tyrosine phosphorylation of insulin receptor beta (IRβ) in insulin treated HepG2 cells is inversely correlated to ser51 phosphorylation in the alpha-subunit of eukaryotic initiation factor 2 (eIF2α) that regulates protein synthesis. Insulin stimulates interaction between IRβ and PKR, double stranded RNA-dependent protein kinase, also known as EIF2AK2, and phosphorylation of tyrosine residues in PKR, as analyzed by immunoprecipitation and pull down assays using anti-IRβ and anti-phosphotyrosine antibodies, recombinant IRβ and immunopurified PKR. Further polyIC or synthetic double stranded RNA-induced threonine phosphorylation or activation of immunopurified and cellular PKR is suppressed in the presence of insulin treated purified IRβ and cell extracts. Acute, but not chronic, insulin treatment enhances tyrosine phosphorylation of IRβ, its interaction with PKR and tyrosine phosphorylation of PKR. In contrast, lipopolysaccharide that stimulates threonine phosphorylation of PKR and eIF2α phosphorylation and AG 1024, an inhibitor of the tyrosine kinase activity of IRβ, reduces PKR association with the receptor, IRβ in HepG2 cells. These findings therefore may suggest that tyrosine phosphorylated PKR plays a role in the regulation of insulin induced protein synthesis and in maintaining insulin sensitivity, whereas, suppression of polyIC-mediated threonine phosphorylation of PKR by insulin compromises its ability to fight against virus infection in host cells. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Biochemistry and Biophysics Elsevier

Insulin treatment promotes tyrosine phosphorylation of PKR and inhibits polyIC induced PKR threonine phosphorylation

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Publisher
Elsevier
Copyright
Copyright © 2015 Elsevier Inc.
ISSN
0003-9861
eISSN
1096-0384
D.O.I.
10.1016/j.abb.2015.07.012
Publisher site
See Article on Publisher Site

Abstract

Tyrosine phosphorylation of insulin receptor beta (IRβ) in insulin treated HepG2 cells is inversely correlated to ser51 phosphorylation in the alpha-subunit of eukaryotic initiation factor 2 (eIF2α) that regulates protein synthesis. Insulin stimulates interaction between IRβ and PKR, double stranded RNA-dependent protein kinase, also known as EIF2AK2, and phosphorylation of tyrosine residues in PKR, as analyzed by immunoprecipitation and pull down assays using anti-IRβ and anti-phosphotyrosine antibodies, recombinant IRβ and immunopurified PKR. Further polyIC or synthetic double stranded RNA-induced threonine phosphorylation or activation of immunopurified and cellular PKR is suppressed in the presence of insulin treated purified IRβ and cell extracts. Acute, but not chronic, insulin treatment enhances tyrosine phosphorylation of IRβ, its interaction with PKR and tyrosine phosphorylation of PKR. In contrast, lipopolysaccharide that stimulates threonine phosphorylation of PKR and eIF2α phosphorylation and AG 1024, an inhibitor of the tyrosine kinase activity of IRβ, reduces PKR association with the receptor, IRβ in HepG2 cells. These findings therefore may suggest that tyrosine phosphorylated PKR plays a role in the regulation of insulin induced protein synthesis and in maintaining insulin sensitivity, whereas, suppression of polyIC-mediated threonine phosphorylation of PKR by insulin compromises its ability to fight against virus infection in host cells.

Journal

Archives of Biochemistry and BiophysicsElsevier

Published: Nov 1, 2015

References

  • Regulation of insulin receptor function
    Youngren, J.F.
  • Phosphorylation of IRS proteins, insulin action, and insulin resistance
    Boura-Halfon, S.; Zick, Y.
  • The IRS-signalling system: a network of docking proteins that mediate insulin action
    White, M.F.
  • Role of the dsRNA-dependent protein kinase (PKR) in the attenuation of protein loss from muscle by insulin and insulin-like growth factor-I (IGF-I)
    Eley, H.L.; Russell, S.T.; Tisdale, M.J.
  • Type 1 phosphatase inhibitors reduce the restoration of guanine nucleotide exchange activity of eukaryotic initiation factor 2B inhibited reticulocyte lysates rescued by Hemin
    Babu, S.V.; Ramaiah, K.V.
  • The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin
    Goh, K.C.; deVeer, M.J.; Williams, B.R.
  • Novel role of PKR in inflammasome activation and HMGB1 release
    Lu, B.; Nakamura, T.; Inouye, K.; Li, J.; Tang, Y.; Lundback, P.; Valdes-Ferrer, S.I.; Olofsson, P.S.; Kalb, T.; Roth, J.; Zou, Y.; Erlandsson-Harris, H.; Yang, H.; Ting, J.P.; Wang, H.; Andersson, U.; Antoine, D.J.; Chavan, S.S.; Hotamisligil, G.S.; Tracey, K.J.

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