c-Jun N-terminal Kinase (JNK) Mediates Feedback Inhibition of the Insulin Signaling Cascade*

Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines inhibits insulin signaling, at least in part, by stimulating phosphorylation of rat/mouse insulin receptor substrate 1 (Irs1) at Ser307(Ser312 in human IRS1). Here we show that JNK mediated feedback inhibition of the insulin signal in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32DIR cells. Insulin stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2 signaling. Moreover, activation of JNK by insulin was inhibited by a cell-permeable peptide that disrupted the interaction of JNK with cellular proteins. However, the direct binding of JNK to Irs1 was not required for its activation by insulin, whereas direct binding was required for Ser307 phosphorylation of Irs1. Insulin-stimulated Ser307 phosphorylation was reduced 80% in cells lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the JNK binding site. Reduced Ser307phosphorylation was directly related to increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and glucose uptake. These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser307 in Irs1.

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

[2]  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.

[3]  Simeon I. Taylor,et al.  Deconstructing Type 2 Diabetes , 1999, Cell.

[4]  S. Schwarze,et al.  In vivo protein transduction: delivery of a biologically active protein into the mouse. , 1999, Science.

[5]  Jianping Ye,et al.  Serine Phosphorylation of Insulin Receptor Substrate 1 by Inhibitor κB Kinase Complex* 210 , 2002, The Journal of Biological Chemistry.

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

[7]  B A Mizock,et al.  Alterations in carbohydrate metabolism during stress: a review of the literature. , 1995, The American journal of medicine.

[8]  A. Ullrich,et al.  The SH2/SH3 domain‐containing protein GRB2 interacts with tyrosine‐phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. , 1993, The EMBO journal.

[9]  M. Lane,et al.  Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. , 1980, The Journal of biological chemistry.

[10]  D. Lambright,et al.  MAP Kinase Signaling Specificity , 2002, Science.

[11]  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.

[12]  Michael Karin,et al.  Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ , 2001, Science.

[13]  M. Kasuga,et al.  Requirement for Protein-tyrosine Phosphatase SHP-2 in Insulin-induced Activation of c-Jun NH2-terminal Kinase* , 2000, The Journal of Biological Chemistry.

[14]  S. Baron.  Salicylates as Hypoglycemic Agents , 1982, Diabetes Care.

[15]  R. Flavell,et al.  Defective T cell differentiation in the absence of Jnk1. , 1998, Science.

[16]  S. Hubbard,et al.  Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain , 1999, Mammalian Genome.

[17]  D. Leroith,et al.  Insulin stimulates PKCzeta -mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins. , 2001, The Journal of biological chemistry.

[18]  M. Lane,et al.  Insulin-dependent phosphorylation of the insulin receptor-protein kinase and activation of glucose transport in 3T3-L1 adipocytes. , 1986, The Journal of biological chemistry.

[19]  D. Bar-Sagi,et al.  Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. , 2000, Science.

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

[21]  P. Rakic,et al.  Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene , 1997, Nature.

[22]  M. White,et al.  Insulin action and type 2 diabetes: lessons from knockout mice: , 1999 .

[23]  J. Yasuda,et al.  A mammalian scaffold complex that selectively mediates MAP kinase activation. , 1998, Science.

[24]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[25]  D. Schorderet,et al.  Cell-Permeable Peptide Inhibitors of JNK: Novel Blockers of β-Cell Death , 2001 .

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

[27]  P. Shapiro,et al.  The Seven-transmembrane-spanning Receptors for Endothelin and Thrombin Cause Proliferation of Airway Smooth Muscle Cells and Activation of the Extracellular Regulated Kinase and c-Jun NH-terminal Kinase Groups of Mitogen-activated Protein Kinases (*) , 1996, The Journal of Biological Chemistry.

[28]  G. Reaven,et al.  Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? , 2000, Free radical biology & medicine.

[29]  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.

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

[31]  W. Simonds,et al.  Signaling from G Protein-coupled Receptors to c-Jun Kinase Involves Subunits of Heterotrimeric G Proteins Acting on a Ras and Rac1-dependent Pathway (*) , 1996, The Journal of Biological Chemistry.

[32]  C. Desbois-Mouthon,et al.  Insulin differentially regulates SAPKs/JNKs and ERKs in CHO cells overexpressing human insulin receptors. , 1998, Biochemical and biophysical research communications.

[33]  E. Wagner,et al.  C-Jun Nh2-Terminal Kinase (Jnk)1 and Jnk2 Have Similar and Stage-Dependent Roles in Regulating T Cell Apoptosis and Proliferation , 2001, The Journal of experimental medicine.

[34]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[35]  M. Karin,et al.  Signal transduction by tumor necrosis factor and its relatives. , 2001, Trends in cell biology.

[36]  D. Barford,et al.  Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. , 2000, Molecular cell.

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

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

[39]  E. Carter.  Insulin resistance in burns and trauma. , 2009, Nutrition reviews.

[40]  D. Hardie,et al.  5′-AMP-activated Protein Kinase Phosphorylates IRS-1 on Ser-789 in Mouse C2C12 Myotubes in Response to 5-Aminoimidazole-4-carboxamide Riboside* , 2001, The Journal of Biological Chemistry.

[41]  Young-Bum Kim,et al.  Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice , 2000, Molecular and Cellular Biology.

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

[43]  M. White,et al.  Regulation of Insulin/Insulin-like Growth Factor-1 Signaling by Proteasome-mediated Degradation of Insulin Receptor Substrate-2* , 2001, The Journal of Biological Chemistry.

[44]  Roger Davis,et al.  The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 * , 2000, The Journal of Biological Chemistry.

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

[46]  G. Shulman,et al.  Disruption of IRS-2 causes type 2 diabetes in mice , 1998, Nature.

[47]  Role of IRS-1-GRB-2 complexes in insulin signaling. , 1994, Molecular and cellular biology.

[48]  M. White,et al.  IRS-4 Mediates Protein Kinase B Signaling during Insulin Stimulation without Promoting Antiapoptosis , 2000, Molecular and Cellular Biology.

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

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

[51]  M. Karin,et al.  Selective activation of the JNK signaling cascadeand c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs , 1995, Cell.

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

[53]  Y. Yazaki,et al.  p110β Is Up-regulated during Differentiation of 3T3-L1 Cells and Contributes to the Highly Insulin-responsive Glucose Transport Activity* , 2000, The Journal of Biological Chemistry.

[54]  R. DeFronzo.  PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[55]  S. Schurmans,et al.  The lipid phosphatase SHIP2 controls insulin sensitivity , 2001, Nature.

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

[57]  G L Johnson,et al.  Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. , 1994, Science.

[58]  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.

[59]  M. White,et al.  Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action* , 2002, The Journal of Biological Chemistry.

[60]  D. Krause,et al.  Transient Activation of Jun N-terminal Kinases and Protection from Apoptosis by the Insulin-like Growth Factor I Receptor Can Be Suppressed by Dicumarol* , 2001, The Journal of Biological Chemistry.