This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Tzatsos, A.
Right arrow Articles by Kandror, K. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tzatsos, A.
Right arrow Articles by Kandror, K. V.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2006, p. 63-76, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.63-76.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation{dagger}

Alexandros Tzatsos* and Konstantin V. Kandror*

Boston University School of Medicine, Boston, Massachusetts 02118

Received 3 December 2004/ Returned for modification 15 February 2005/ Accepted 3 October 2005

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y632MPM motif that is implicated in the binding of p85{alpha}/p110{alpha} PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

* Corresponding author. Present address for Alexandros Tzatsos: Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington St., Box 5609, Boston, MA 02111. Phone: (617) 636-6153. Fax: (617) 636-6127. E-mail: atzatsos{at}tufts-nemc.org. Mailing address for Konstantin V. Kandror: Boston University School of Medicine, Department of Biochemistry, 715 Albany Street, Boston, MA 02118. Phone: (617) 638-5049. Fax: (617) 638-5339. kandror{at}biochem.bumc.bu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2006, p. 63-76, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.63-76.2006
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]  
  • Reynolds, T. H. IV, Cinquino, N., Anthony, M., Phelps, C. B., Zachary Berk, E. (2009). Insulin resistance without elevated mammalian target of rapamycin complex 1 activity in muscles of mice fed a high-fat diet. J. Appl. Physiol. 107: 1479-1485 [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]  
  • Zhang, C., Yoon, M.-S., Chen, J. (2009). Amino acid-sensing mTOR signaling is involved in modulation of lipolysis by chronic insulin treatment in adipocytes. Am. J. Physiol. Endocrinol. Metab. 296: E862-E868 [Abstract] [Full Text]  
  • Deepa, S. S., Dong, L. Q. (2009). APPL1: role in adiponectin signaling and beyond. Am. J. Physiol. Endocrinol. Metab. 296: E22-E36 [Abstract] [Full Text]  
  • Horike, N., Sakoda, H., Kushiyama, A., Ono, H., Fujishiro, M., Kamata, H., Nishiyama, K., Uchijima, Y., Kurihara, Y., Kurihara, H., Asano, T. (2008). AMP-activated Protein Kinase Activation Increases Phosphorylation of Glycogen Synthase Kinase 3{beta} and Thereby Reduces cAMP-responsive Element Transcriptional Activity and Phosphoenolpyruvate Carboxykinase C Gene Expression in the Liver. J. Biol. Chem. 283: 33902-33910 [Abstract] [Full Text]  
  • Miller, A. M., Brestoff, J. R., Phelps, C. B., Berk, E. Z., Reynolds, T. H. IV (2008). Rapamycin does not improve insulin sensitivity despite elevated mammalian target of rapamycin complex 1 activity in muscles of ob/ob mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295: R1431-R1438 [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]  
  • Anderson, N., Borlak, J. (2008). Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis. Pharmacol. Rev. 60: 311-357 [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]  
  • Radhakrishnan, Y., Maile, L. A., Ling, Y., Graves, L. M., Clemmons, D. R. (2008). Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells. J. Biol. Chem. 283: 16320-16331 [Abstract] [Full Text]  
  • Robinson, K. A., Buse, M. G. (2008). Mechanisms of high-glucose/insulin-mediated desensitization of acute insulin-stimulated glucose transport and Akt activation. Am. J. Physiol. Endocrinol. Metab. 294: E870-E881 [Abstract] [Full Text]  
  • Cederroth, C. R., Vinciguerra, M., Gjinovci, A., Kuhne, F., Klein, M., Cederroth, M., Caille, D., Suter, M., Neumann, D., James, R. W., Doerge, D. R., Wallimann, T., Meda, P., Foti, M., Rohner-Jeanrenaud, F., Vassalli, J.-D., Nef, S. (2008). Dietary Phytoestrogens Activate AMP-Activated Protein Kinase With Improvement in Lipid and Glucose Metabolism. Diabetes 57: 1176-1185 [Abstract] [Full Text]  
  • Waraich, R. S., Weigert, C., Kalbacher, H., Hennige, A. M., Lutz, S. Z., Haring, H.-U., Schleicher, E. D., Voelter, W., Lehmann, R. (2008). Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-{delta} on Insulin Action in Skeletal Muscle Cells. J. Biol. Chem. 283: 11226-11233 [Abstract] [Full Text]  
  • Fraenkel, M., Ketzinel-Gilad, M., Ariav, Y., Pappo, O., Karaca, M., Castel, J., Berthault, M.-F., Magnan, C., Cerasi, E., Kaiser, N., Leibowitz, G. (2008). mTOR Inhibition by Rapamycin Prevents {beta}-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes. Diabetes 57: 945-957 [Abstract] [Full Text]  
  • Koketsu, Y., Sakoda, H., Fujishiro, M., Kushiyama, A., Fukushima, Y., Ono, H., Anai, M., Kikuchi, T., Fukuda, T., Kamata, H., Horike, N., Uchijima, Y., Kurihara, H., Asano, T. (2008). Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice. Am. J. Physiol. Endocrinol. Metab. 294: E719-E725 [Abstract] [Full Text]  
  • Kim, J.-H., Kim, J. E., Liu, H.-Y., Cao, W., Chen, J. (2008). Regulation of Interleukin-6-induced Hepatic Insulin Resistance by Mammalian Target of Rapamycin through the STAT3-SOCS3 Pathway. J. Biol. Chem. 283: 708-715 [Abstract] [Full Text]  
  • Martin, K. A., Merenick, B. L., Ding, M., Fetalvero, K. M., Rzucidlo, E. M., Kozul, C. D., Brown, D. J., Chiu, H. Y., Shyu, M., Drapeau, B. L., Wagner, R. J., Powell, R. J. (2007). Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling. J. Biol. Chem. 282: 36112-36120 [Abstract] [Full Text]  
  • Luo, M., Langlais, P., Yi, Z., Lefort, N., De Filippis, E. A., Hwang, H., Christ-Roberts, C. Y., Mandarino, L. J. (2007). Phosphorylation of Human Insulin Receptor Substrate-1 at Serine 629 Plays a Positive Role in Insulin Signaling. Endocrinology 148: 4895-4905 [Abstract] [Full Text]  
  • Gregor, M. F., Hotamisligil, G. S. (2007). Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J. Lipid Res. 48: 1905-1914 [Abstract] [Full Text]  
  • Woo, S.-Y., Kim, D.-H., Jun, C.-B., Kim, Y.-M., Haar, E. V., Lee, S.-i., Hegg, J. W., Bandhakavi, S., Griffin, T. J., Kim, D.-H. (2007). PRR5, a Novel Component of mTOR Complex 2, Regulates Platelet-derived Growth Factor Receptor beta Expression and Signaling. J. Biol. Chem. 282: 25604-25612 [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]  
  • Guo, W., Wong, S., Xie, W., Lei, T., Luo, Z. (2007). Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes. Am. J. Physiol. Endocrinol. Metab. 293: E576-E586 [Abstract] [Full Text]  
  • Canabal, D. D., Potian, J. G., Duran, R. G., McArdle, J. J., Routh, V. H. (2007). Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R592-R600 [Abstract] [Full Text]  
  • de Borst, M. H., Diks, S. H., Bolbrinker, J., Schellings, M. W., van Dalen, M. B. A., Peppelenbosch, M. P., Kreutz, R., Pinto, Y. M., Navis, G., van Goor, H. (2007). Profiling of the renal kinome: a novel tool to identify protein kinases involved in angiotensin II-dependent hypertensive renal damage. Am. J. Physiol. Renal Physiol. 293: F428-F437 [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]  
  • Tzatsos, A., Tsichlis, P. N. (2007). Energy Depletion Inhibits Phosphatidylinositol 3-Kinase/Akt Signaling and Induces Apoptosis via AMP-activated Protein Kinase-dependent Phosphorylation of IRS-1 at Ser-794. J. Biol. Chem. 282: 18069-18082 [Abstract] [Full Text]  
  • Wang, C., Mao, X., Wang, L., Liu, M., Wetzel, M. D., Guan, K.-L., Dong, L. Q., Liu, F. (2007). Adiponectin Sensitizes Insulin Signaling by Reducing p70 S6 Kinase-mediated Serine Phosphorylation of IRS-1. J. Biol. Chem. 282: 7991-7996 [Abstract] [Full Text]  
  • Sherry, C. L., O'Connor, J. C., Kramer, J. M., Freund, G. G. (2007). Augmented Lipopolysaccharide-Induced TNF-{alpha} Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK. J. Immunol. 178: 663-670 [Abstract] [Full Text]  
  • Roudier, E., Mistafa, O., Stenius, U. (2006). Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs.. Molecular Cancer Therapeutics 5: 2706-2715 [Abstract] [Full Text]  
  • Shah, O. J., Hunter, T. (2006). Turnover of the Active Fraction of IRS1 Involves Raptor-mTOR- and S6K1-Dependent Serine Phosphorylation in Cell Culture Models of Tuberous Sclerosis.. Mol. Cell. Biol. 26: 6425-6434 [Abstract] [Full Text]  
  • Bertrand, L., Ginion, A., Beauloye, C., Hebert, A. D., Guigas, B., Hue, L., Vanoverschelde, J.-L. (2006). AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B. Am. J. Physiol. Heart Circ. Physiol. 291: H239-H250 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»