The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 *

Tumor necrosis factor α (TNFα) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNFα promotes multipotential signal transduction cascades, including the activation of the Jun NH2-terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFα on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFα on IRS-1 function.

[1]  D. Leroith,et al.  Phosphorylation of Insulin Receptor Substrate-1 (IRS-1) by Protein Kinase B Positively Regulates IRS-1 Function* , 1999, The Journal of Biological Chemistry.

[2]  Roger J. Davis,et al.  The JIP Group of Mitogen-Activated Protein Kinase Scaffold Proteins , 1999, Molecular and Cellular Biology.

[3]  M. White,et al.  Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling , 1999, Nature Genetics.

[4]  R. Dantzer,et al.  A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  N. Rothwell,et al.  Mechanisms of tumor necrosis factor alpha action on neurodegeneration: interaction with insulin-like growth factor-1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Goldberg,et al.  Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. , 1999, Diabetes.

[7]  G. Hotamisligil.  The role of TNFα and TNF receptors in obesity and insulin resistance , 1999 .

[8]  J. Russell,et al.  Identification of Enhanced Serine Kinase Activity in Insulin Resistance* , 1999, The Journal of Biological Chemistry.

[9]  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.

[10]  C. Kahn,et al.  Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. , 1999, The Journal of clinical investigation.

[11]  P. Rakic,et al.  The Jnk1 and Jnk2 Protein Kinases Are Required for Regional Specific Apoptosis during Early Brain Development , 1999, Neuron.

[12]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[13]  D L Rothman,et al.  Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. , 1999, The Journal of clinical investigation.

[14]  R. Davis,et al.  Signal transduction by the c-Jun N-terminal kinase. , 1999, Biochemical Society symposium.

[15]  R. Flavell,et al.  The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ Thymocytes , 1998, The Journal of experimental medicine.

[16]  M. White,et al.  The Pleckstrin Homology and Phosphotyrosine Binding Domains of Insulin Receptor Substrate 1 Mediate Inhibition of Apoptosis by Insulin , 1998, Molecular and Cellular Biology.

[17]  J. Olefsky,et al.  Platelet-derived Growth Factor Inhibits Insulin Stimulation of Insulin Receptor Substrate-1-associated Phosphatidylinositol 3-Kinase in 3T3-L1 Adipocytes without Affecting Glucose Transport* , 1998, The Journal of Biological Chemistry.

[18]  J. Kyriakis,et al.  Tumor Necrosis Factor Signaling to Stress-activated Protein Kinase (SAPK)/Jun NH2-terminal Kinase (JNK) and p38 , 1998, The Journal of Biological Chemistry.

[19]  Y. Ip,et al.  Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. , 1998, Current opinion in cell biology.

[20]  A. Sharrocks,et al.  Differential targeting of MAP kinases to the ETS‐domain transcription factor Elk‐1 , 1998, The EMBO journal.

[21]  A. Barthel,et al.  Protein kinase C modulates the insulin-stimulated increase in Akt1 and Akt3 activity in 3T3-L1 adipocytes. , 1998, Biochemical and Biophysical Research Communications - BBRC.

[22]  P. Boutin,et al.  A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. , 1998, The Journal of clinical investigation.

[23]  P. Cohen,et al.  Mechanism of activation and function of protein kinase B. , 1998, Current opinion in genetics & development.

[24]  Roger J. Davis,et al.  Selective Activation of p38 Mitogen-activated Protein (MAP) Kinase Isoforms by the MAP Kinase Kinases MKK3 and MKK6* , 1998, The Journal of Biological Chemistry.

[25]  B. Zlokovic,et al.  Circulating Antibody against Tumor Necrosis Factor–Alpha Protects Rat Brain from Reperfusion Injury , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[27]  R. Roth,et al.  Modulation of Insulin Receptor Substrate-1 Tyrosine Phosphorylation and Function by Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[28]  D. Leroith,et al.  A Molecular Basis for Insulin Resistance , 1997, The Journal of Biological Chemistry.

[29]  R A Roth,et al.  Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. , 1997, Biochemistry.

[30]  K. Uysal,et al.  Protection from obesity-induced insulin resistance in mice lacking TNF-α function , 1997, Nature.

[31]  R. Tompkins,et al.  Analysis of Thermal Injury-induced Insulin Resistance in Rodents , 1997, The Journal of Biological Chemistry.

[32]  M E Greenberg,et al.  A cytoplasmic inhibitor of the JNK signal transduction pathway. , 1997, Science.

[33]  R. Willette,et al.  Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. , 1997, Stroke.

[34]  M. White,et al.  The IRS‐signalling system during insulin and cytokine action , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[35]  G. Lathrop,et al.  Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3). , 1997, Human molecular genetics.

[36]  J. Gutkind,et al.  Requirement of phosphatidylinositol-3 kinase for activation of JNK/SAPKs by PDGF. , 1997, Biochemical and biophysical research communications.

[37]  H. Nawashiro,et al.  Inhibition of Tumor Necrosis Factor and Amelioration of Brain Infarction in Mice , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[38]  C. Malbon,et al.  jun N-terminal Kinase Mediates Activation of Skeletal Muscle Glycogen Synthase by Insulin in Vivo* , 1996, The Journal of Biological Chemistry.

[39]  J. Avruch,et al.  Sounding the Alarm: Protein Kinase Cascades Activated by Stress and Inflammation* , 1996, The Journal of Biological Chemistry.

[40]  Lynne Yenush,et al.  The Pleckstrin Homology Domain Is the Principle Link between the Insulin Receptor and IRS-1* , 1996, The Journal of Biological Chemistry.

[41]  U. Shankavaram,et al.  Activation of cJun NH2-terminal kinase/stress-activated protein kinase by insulin. , 1996, Biochemistry.

[42]  B. Spiegelman,et al.  Tumor Necrosis Factor (TNF)-α Inhibits Insulin Signaling through Stimulation of the p55 TNF Receptor and Activation of Sphingomyelinase* , 1996, The Journal of Biological Chemistry.

[43]  E. Van Obberghen,et al.  Phosphorylation of Insulin Receptor Substrate-1 on Multiple Serine Residues, 612, 632, 662, and 731, Modulates Insulin Action (*) , 1996, The Journal of Biological Chemistry.

[44]  A. Ullrich,et al.  Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. , 1996, The Journal of clinical investigation.

[45]  B. Spiegelman,et al.  IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance , 1996, Science.

[46]  M. Papa,et al.  Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. , 1995, The Journal of biological chemistry.

[47]  William Arbuthnot Sir Lane,et al.  Role of IRS-2 in insulin and cytokine signalling , 1995, Nature.

[48]  R. Hipskind,et al.  Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1 , 1995, Molecular and cellular biology.

[49]  M. White,et al.  The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase , 1995, Molecular and cellular biology.

[50]  J. Blenis,et al.  The Pleckstrin Homology Domain in Insulin Receptor Substrate-1 Sensitizes Insulin Signaling (*) , 1995, The Journal of Biological Chemistry.

[51]  M. Barbacid,et al.  Farnesyltransferase inhibitors are inhibitors of Ras but not R-Ras2/TC21, transformation. , 1995, Oncogene.

[52]  Jiahuai Han,et al.  Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*) , 1995, The Journal of Biological Chemistry.

[53]  B. Dérijard,et al.  Transcription factor ATF2 regulation by the JNK signal transduction pathway , 1995, Science.

[54]  L. Mahadevan,et al.  Anisomycin-activated protein kinases p45 and p55 but not mitogen-activated protein kinases ERK-1 and -2 are implicated in the induction of c-fos and c-jun , 1994, Molecular and cellular biology.

[55]  B. Spiegelman,et al.  Tumor Necrosis Factor α: A Key Component of the Obesity-Diabetes Link , 1994, Diabetes.

[56]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[57]  M. White,et al.  Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1 , 1993, Molecular and cellular biology.

[58]  C. Kahn,et al.  Insulin stimulates serine and tyrosine phosphorylation in the juxtamembrane region of the insulin receptor. , 1993, The Journal of biological chemistry.

[59]  M. White,et al.  The New Elements of Insulin Signaling: Insulin Receptor Substrate-1 and Proteins With SH2 Domains , 1993, Diabetes.

[60]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[61]  C. Kahn,et al.  Expression and function of IRS-1 in insulin signal transmission. , 1992, The Journal of biological chemistry.

[62]  C. Kahn,et al.  Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein , 1991, Nature.

[63]  K. Hagino-Yamagishi,et al.  [Oncogene]. , 2019, Gan to kagaku ryoho. Cancer & chemotherapy.

[64]  S. Roseman,et al.  Glucosamine metabolism. IV. Glucosamine-6-phosphate deaminase. , 1958, The Journal of biological chemistry.