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

ABSTRACT 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 p85α/p110α 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.

[1]  B V Howard,et al.  Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. , 1988, The New England journal of medicine.

[2]  J. Bigby Harrison's Principles of Internal Medicine , 1988 .

[3]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[4]  Richard Barnett,et al.  Diabetes mellitus. , 1993, The Medical journal of Australia.

[5]  G. Boss,et al.  Determination of absolute amounts of GDP and GTP bound to Ras in mammalian cells: comparison of parental and Ras-overproducing NIH 3T3 fibroblasts. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Avruch,et al.  Multiple independent inputs are required for activation of the p70 S6 kinase , 1995, Molecular and cellular biology.

[7]  J. Blenis,et al.  Structural and functional analysis of pp70S6k. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  G Dailey,et al.  Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. , 1995, The New England journal of medicine.

[9]  J. Avruch,et al.  Phosphatidylinositol 3-kinase signals activation of p70 S6 kinase in situ through site-specific p70 phosphorylation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Blenis,et al.  YMXM motifs and signaling by an insulin receptor substrate 1 molecule without tyrosine phosphorylation sites , 1996, Molecular and cellular biology.

[11]  G. Thomas,et al.  The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases , 1996, Molecular and cellular biology.

[12]  M. Yaffe,et al.  The Structural Basis for 14-3-3:Phosphopeptide Binding Specificity , 1997, Cell.

[13]  T. Haystead,et al.  The Mammalian Target of Rapamycin Phosphorylates Sites Having a (Ser/Thr)-Pro Motif and Is Activated by Antibodies to a Region near Its COOH Terminus , 1997, The Journal of Biological Chemistry.

[14]  U. Smith,et al.  Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[16]  R. Pearson,et al.  Dual requirement for a newly identified phosphorylation site in p70s6k , 1997, Molecular and cellular biology.

[17]  C. Kahn,et al.  Dynamics of Insulin Signaling in 3T3-L1 Adipocytes , 1998, The Journal of Biological Chemistry.

[18]  M. Andjelkovic,et al.  Phosphorylation and activation of p70s6k by PDK1. , 1998, Science.

[19]  C. Kahn,et al.  Bidirectional modulation of insulin action by amino acids. , 1998, The Journal of clinical investigation.

[20]  S. Snyder,et al.  RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Joseph Avruch,et al.  Regulation of the p70 S6 Kinase by Phosphorylation in Vivo , 1998, The Journal of Biological Chemistry.

[22]  K. Kaneko,et al.  Characterization of the phosphoproteins and protein kinase activity in mTOR immunoprecipitates. , 1998, Biochemical and biophysical research communications.

[23]  L. Groop,et al.  Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  R. Roth,et al.  Modulation of Insulin Receptor Substrate-1 Tyrosine Phosphorylation by an Akt/Phosphatidylinositol 3-Kinase Pathway* , 1999, The Journal of Biological Chemistry.

[25]  Z Trajanoski,et al.  Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. , 1999, The New England journal of medicine.

[26]  Kenta Hara,et al.  Immunopurified Mammalian Target of Rapamycin Phosphorylates and Activates p70 S6 Kinase α in Vitro * , 1999, The Journal of Biological Chemistry.

[27]  G. Shulman,et al.  On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance , 2022 .

[28]  D. James,et al.  Release of Insulin Receptor Substrate Proteins from an Intracellular Complex Coincides with the Development of Insulin Resistance* , 2000, The Journal of Biological Chemistry.

[29]  Margaret S. Wu,et al.  Role of AMP-activated protein kinase in mechanism of metformin action. , 2001, The Journal of clinical investigation.

[30]  A. Marette,et al.  Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. , 2001, The Journal of biological chemistry.

[31]  M. Quon,et al.  Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells. , 2001, Endocrinology.

[32]  A. Papavassiliou,et al.  Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance. , 2001, Molecular endocrinology.

[33]  L. Mayo,et al.  A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Kahn,et al.  Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. , 2001, The Journal of clinical investigation.

[35]  J. Chen,et al.  Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. , 2001, Biochemical and biophysical research communications.

[36]  Olle Ljunqvist,et al.  Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. , 2002, Diabetes.

[37]  D. Sabatini,et al.  mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery , 2002, Cell.

[38]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[39]  J. Crespo,et al.  Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. , 2002, Molecular cell.

[40]  D. Carling,et al.  Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. , 2002, Diabetes.

[41]  R. Somwar,et al.  Sustained exposure of L6 myotubes to high glucose and insulin decreases insulin-stimulated GLUT4 translocation but upregulates GLUT4 activity. , 2002, Diabetes.

[42]  J. Avruch,et al.  Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action , 2002, Cell.

[43]  Junying Yuan,et al.  LKB1 — A master tumour suppressor of the small intestine and beyond , 2002, Nature Reviews Cancer.

[44]  P. Brennan,et al.  Regulation of an Activated S6 Kinase 1 Variant Reveals a Novel Mammalian Target of Rapamycin Phosphorylation Site* , 2002, The Journal of Biological Chemistry.

[45]  J. Blenis,et al.  Identification of a Conserved Motif Required for mTOR Signaling , 2002, Current Biology.

[46]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[47]  B. Edgar,et al.  Rheb promotes cell growth as a component of the insulin/TOR signalling network , 2003, Nature Cell Biology.

[48]  J. Avruch,et al.  The Mammalian Target of Rapamycin (mTOR) Partner, Raptor, Binds the mTOR Substrates p70 S6 Kinase and 4E-BP1 through Their TOR Signaling (TOS) Motif* , 2003, The Journal of Biological Chemistry.

[49]  Y. Le Marchand-Brustel,et al.  Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. , 2003, Diabetes.

[50]  B. Viollet,et al.  The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. , 2003, The Journal of clinical investigation.

[51]  J. Blenis,et al.  TOS Motif-Mediated Raptor Binding Regulates 4E-BP1 Multisite Phosphorylation and Function , 2003, Current Biology.

[52]  K. Inoki,et al.  Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. , 2003, Genes & development.

[53]  E. Van Obberghen,et al.  Phosphoinositide 3-Kinase-mediated Reduction of Insulin Receptor Substrate-1/2 Protein Expression via Different Mechanisms Contributes to the Insulin-induced Desensitization of Its Signaling Pathways in L6 Muscle Cells* , 2003, The Journal of Biological Chemistry.

[54]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[55]  T. Hunter,et al.  Inappropriate Activation of the TSC/Rheb/mTOR/S6K Cassette Induces IRS1/2 Depletion, Insulin Resistance, and Cell Survival Deficiencies , 2004, Current Biology.

[56]  S. Gygi,et al.  SKAR Is a Specific Target of S6 Kinase 1 in Cell Growth Control , 2004, Current Biology.

[57]  R. Loewith,et al.  Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive , 2004, Nature Cell Biology.

[58]  Johan Auwerx,et al.  Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity , 2004, Nature.

[59]  R. DePinho,et al.  Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. , 2004, Genes & development.

[60]  D. Guertin,et al.  Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton , 2004, Current Biology.

[61]  Jérôme Boudeau,et al.  LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1 , 2004, The EMBO journal.

[62]  S. Biswas,et al.  Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. , 2004, The Biochemical journal.

[63]  David Carling,et al.  The AMP-activated protein kinase cascade--a unifying system for energy control. , 2004, Trends in biochemical sciences.

[64]  N. Tennagels,et al.  In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. , 2004, Biochemistry.

[65]  K. Inoki,et al.  Biochemical and Functional Characterizations of Small GTPase Rheb and TSC2 GAP Activity , 2004, Molecular and Cellular Biology.

[66]  R. DePinho,et al.  The LKB1 tumor suppressor negatively regulates mTOR signaling. , 2004, Cancer cell.

[67]  Lewis C Cantley,et al.  The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[68]  S. Shoelson,et al.  Insulin Resistance Due to Phosphorylation of Insulin Receptor Substrate-1 at Serine 302* , 2004, Journal of Biological Chemistry.

[69]  I. Gout,et al.  The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins , 2004, The Journal of cell biology.

[70]  J. Avruch,et al.  Dissociation of raptor from mTOR is a mechanism of rapamycin‐induced inhibition of mTOR function , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[71]  A. Marette,et al.  Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. , 2005, Endocrinology.

[72]  J. Avruch,et al.  Rheb Binding to Mammalian Target of Rapamycin (mTOR) Is Regulated by Amino Acid Sufficiency* , 2005, Journal of Biological Chemistry.

[73]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[74]  Joseph Avruch,et al.  Rheb Binds and Regulates the mTOR Kinase , 2005, Current Biology.

[75]  D. Sabatini,et al.  Structure of S6 Kinase 1 Determines whether Raptor-mTOR or Rictor-mTOR Phosphorylates Its Hydrophobic Motif Site*♦ , 2005, Journal of Biological Chemistry.

[76]  Kei Sakamoto,et al.  Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction , 2005, The EMBO journal.