Participation of ATM in insulin signalling through phosphorylation of elF-4E-binding protein 1

D. Q. Yang, M. B. Kastan

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228 Scopus citations

Abstract

One of the critical responses to insulin treatment is the stimulation of protein synthesis through induced phosphorylation of the elF-4E-binding protein 1 (4E-BP1), and the subsequent release of the translation initiation factor elF-4E. Here we report that ATM, the protein product of the ATM gene that is mutated in the disease ataxia telangiectasia, phosphorylates 4E-BP1 at Ser 111 in vitro and that insulin treatment induces phosphorylation of 4E-BP1 at Ser 111 in rive in an ATM-dependent manner. In addition, insulin treatment of cells enhances the specific kinase activity of ATM. Cells lacking ATM kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4E-BP1 from elF-4E. These results suggest an unexpected role for ATM in an insulin-signalling pathway that controls translation initiation. Through this mechanism, a lack of ATM activity probably contributes to some of the metabolic abnormalities, such as poor growth and insulin resistance, reported in ataxia telangiectasia cells and patients with ataxia telangiectasia.

Original languageEnglish (US)
Pages (from-to)893-898
Number of pages6
JournalNature Cell Biology
Volume2
Issue number12
DOIs
StatePublished - 2000
Externally publishedYes

Bibliographical note

Funding Information:
ACKNOWLEDGEMENTS We thank T. M. Gilmer and Y. Shiloh for monoclonal antibodies to ATM; D. Sabatini for 4E-BP1 and eIF-4E cDNA reagents; P. Leder for AT-null murine fibroblasts; A. Friedman for Mouse 3T3 L1 cells. We also thank P. Houghton and J. C. Jones for helpful comments on the manuscript, and C. Canman, D-S. Lim, S-T. Kim, D. Woods and A. Justman for advice and technical assistance. This work was supported by grants from the NIH. M.B.K. is also supported by the American Lebanese Syrian Associated Charities (ALSAC) of the St. Jude Children’s Research Hospital. Correspondence and requests for materials should be addressed to: M.B.K. (e-mail: Michael.Kastan@stjude.org).

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