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

Nature Cell Biology volume 2, pages 893–898 (2000)Cite this article

Abstract

One of the critical responses to insulin treatment is the stimulation of protein synthesis through induced phosphorylation of the eIF-4E-binding protein 1 (4E-BP1), and the subsequent release of the translation initiation factor, eIF-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 vivo 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 eIF-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.

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Figure 1: Phosphorylation of Ser 111 in rat 4E-BP1 by ATM in vitro.
Figure 2: ATM phosphorylation of 4E-BP1 after insulin stimulation.
Figure 3: In vivo phosphorylation of Ser 111 of bound 4E-BP1 in cells co-transfected with wild-type (WT) or kinase-dead (KD) ATM.
Figure 4: Comparison of the release of bound 4E-BP1 from eIF-4E in different cell types as a function of ATM status after insulin treatment.
Figure 5: Proposed model for the signalling process involving phosphorylation of 4E-BP1 bound to eIF-4E.

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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.

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  1. Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, 38105-2794, Tennessee, USA

    Da-Qing Yang & Michael B. Kastan

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Correspondence to Michael B. Kastan.

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Yang, DQ., Kastan, M. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol 2, 893–898 (2000). https://doi.org/10.1038/35046542

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