This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shah, O. J.
Right arrow Articles by Hunter, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shah, O. J.
Right arrow Articles by Hunter, T.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2006, p. 6425-6434, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.01254-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Turnover of the Active Fraction of IRS1 Involves Raptor-mTOR- and S6K1-Dependent Serine Phosphorylation in Cell Culture Models of Tuberous Sclerosis

O. Jameel Shah1,2 and Tony Hunter1*

Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037,1 Abbott Laboratories, Global Pharmaceutical Research and Development, Cancer Biology Division, 100 Abbott Park Road, Abbott Park, Illinois 600642

Received 2 July 2005/ Returned for modification 17 August 2005/ Accepted 12 June 2006

The TSC1-TSC2/Rheb/Raptor-mTOR/S6K1 cell growth cassette has recently been shown to regulate cell autonomous insulin and insulin-like growth factor I (IGF-I) sensitivity by transducing a negative feedback signal that targets insulin receptor substrates 1 and 2 (IRS1 and -2). Using two cell culture models of the familial hamartoma syndrome, tuberous sclerosis, we show here that Raptor-mTOR and S6K1 are required for phosphorylation of IRS1 at a subset of serine residues frequently associated with insulin resistance, including S307, S312, S527, S616, and S636 (of human IRS1). Using loss- and gain-of-function S6K1 constructs, we demonstrate a requirement for the catalytic activity of S6K1 in both direct and indirect regulation of IRS1 serine phosphorylation. S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T,P sites. IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb. These studies suggest that, through serine phosphorylation, Raptor-mTOR and S6K1 cell autonomously promote the depletion of IRS1 from specific intracellular pools in pathological states of insulin and IGF-I resistance and thus potentially in lesions associated with tuberous sclerosis.

* Corresponding author. Mailing address: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 453-4100, ext. 1385. Fax: (858) 457-4765. E-mail: hunter{at}salk.edu.

Molecular and Cellular Biology, September 2006, p. 6425-6434, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.01254-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dibble, C. C., Asara, J. M., Manning, B. D. (2009). Characterization of Rictor Phosphorylation Sites Reveals Direct Regulation of mTOR Complex 2 by S6K1. Mol. Cell. Biol. 29: 5657-5670 [Abstract] [Full Text]  
  • Mahimainathan, L., Ghosh-Choudhury, N., Venkatesan, B., Das, F., Mandal, C. C., Dey, N., Habib, S. L., Kasinath, B. S., Abboud, H. E., Ghosh Choudhury, G. (2009). TSC2 Deficiency Increases PTEN via HIF1{alpha}. J. Biol. Chem. 284: 27790-27798 [Abstract] [Full Text]  
  • Standen, C. L., Kennedy, N. J., Flavell, R. A., Davis, R. J. (2009). Signal Transduction Cross Talk Mediated by Jun N-Terminal Kinase-Interacting Protein and Insulin Receptor Substrate Scaffold Protein Complexes. Mol. Cell. Biol. 29: 4831-4840 [Abstract] [Full Text]  
  • Tzatsos, A. (2009). Raptor Binds the SAIN (Shc and IRS-1 NPXY Binding) Domain of Insulin Receptor Substrate-1 (IRS-1) and Regulates the Phosphorylation of IRS-1 at Ser-636/639 by mTOR. J. Biol. Chem. 284: 22525-22534 [Abstract] [Full Text]  
  • Parathath, S. R., Mainwaring, L. A., Fernandez-L, A., Campbell, D. O., Kenney, A. M. (2008). Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors. Development 135: 3291-3300 [Abstract] [Full Text]  
  • Huang, J., Dibble, C. C., Matsuzaki, M., Manning, B. D. (2008). The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2. Mol. Cell. Biol. 28: 4104-4115 [Abstract] [Full Text]  
  • Dan, H. C., Cooper, M. J., Cogswell, P. C., Duncan, J. A., Ting, J. P.-Y., Baldwin, A. S. (2008). Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev. 22: 1490-1500 [Abstract] [Full Text]  
  • Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., Chin, L., DePinho, R. A., Cavenee, W. K. (2007). Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21: 2683-2710 [Abstract] [Full Text]  
  • Tremblay, F., Brule, S., Hee Um, S., Li, Y., Masuda, K., Roden, M., Sun, X. J., Krebs, M., Polakiewicz, R. D., Thomas, G., Marette, A. (2007). Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc. Natl. Acad. Sci. USA 104: 14056-14061 [Abstract] [Full Text]  
  • Barbour, L. A., McCurdy, C. E., Hernandez, T. L., Kirwan, J. P., Catalano, P. M., Friedman, J. E. (2007). Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes. Diabetes Care 30: S112-S119 [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»