DOI: 10.1073/pnas.94.18.9660. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action

Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action

10.1073/pnas.94.18.9660

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The phosphorylation of insulin receptor substrate 1 (IRS-1) on tyrosine residues by the insulin receptor (IR) tyrosine kinase is involved in most of the biological responses of insulin. IRS-1 mediates insulin signaling by recruiting SH2 proteins through its multiple tyrosine phosphorylation sites. The phosphorylation of IRS-1 on serine/threonine residues also occurs in cells; however, the particular protein kinase(s) promoting this type of phosphorylation are unknown. Here we report that glycogen synthase kinase 3 (GSK-3) is capable of phosphorylating IRS-1 and that this modification converts IRS-1 into an inhibitor of IR tyrosine kinase activity in vitro . Expression of wild-type GSK-3 or an “unregulated” mutant of the kinase (S9A) in CHO cells overexpressing IRS-1 and IR, resulted in increased serine phosphorylation levels of IRS-1, suggesting that IRS-1 is a cellular target of GSK-3. Furthermore, insulin-induced tyrosine phosphorylation of IRS-1 and IR was markedly suppressed in cells expressing wild-type or the S9A mutant, indicating that expression of GSK-3 impairs IR tyrosine kinase activity. Taken together, our studies suggest a new role for GSK-3 in attenuating insulin signaling via its phosphorylation of IRS-1 and may provide new insight into mechanisms important in insulin resistance.

Bibliography

Eldar-Finkelman, H., & Krebs, E. G. (1997). Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proceedings of the National Academy of Sciences, 94(18), 9660â9664.

Authors 2

Hagit Eldar-Finkelman (first)
Edwin G. Krebs (additional)

References 39 Referenced 247

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:35 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 3:02 p.m.)
Indexed	4 weeks, 2 days ago (Aug. 6, 2025, 8:32 a.m.)
Issued	28 years ago (Sept. 2, 1997)
Published	28 years ago (Sept. 2, 1997)
Published Online	28 years ago (Sept. 2, 1997)
Published Print	28 years ago (Sept. 2, 1997)

Funders 0

None

BibTeX

@article{Eldar_Finkelman_1997, title={Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.18.9660}, DOI={10.1073/pnas.94.18.9660}, number={18}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Eldar-Finkelman, Hagit and Krebs, Edwin G.}, year={1997}, month=sep, pages={9660–9664} }

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