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Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action*

  • Vincent Aguirre
    Affiliations
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
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  • Eric D. Werner
    Affiliations
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
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  • Jodel Giraud
    Affiliations
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
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  • Yong Hee Lee
    Footnotes
    Affiliations
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
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  • Steve E. Shoelson
    Affiliations
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
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  • Morris F. White
    Correspondence
    To whom correspondence should be addressed: Howard Hughes Medical Inst., Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215. Tel.: 617-732-2578; Fax: 617-732-2593
    Affiliations
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
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  • Author Footnotes
    * The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
    ‡ Supported in part by the Korean Science and Engineering Foundation.
Open AccessPublished:October 17, 2001DOI:https://doi.org/10.1074/jbc.M101521200
      Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin signal transduction in a variety of cell backgrounds, which might contribute to peripheral insulin resistance. However, because of the large number of potential phosphorylation sites, the mechanism of inhibition has been difficult to determine. One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser307in rat IRS-1 or Ser312 in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. During a yeast tri-hybrid assay, phosphorylation of Ser307 by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. In 32D myeloid progenitor cells, phosphorylation of Ser307 inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser307 (Ser312 in human IRS-1) might be a general mechanism to regulate insulin signaling.
      IRS
      insulin receptor substrate
      TNF
      tumor necrosis factor
      JNK
      c-Jun N-terminal kinase
      PTB
      phosphotyrosine-binding
      MAPK
      mitogen-activated protein kinase
      IGF-1
      insulin-like growth factor-1
      GST
      glutathioneS-transferase
      JIP
      JNK-interacting protein
      PI3K
      phosphatidylinositol 3-kinase
      IR
      insulin receptor
      SD
      synthetic dextrose
      ERK
      extracellular signal-regulated kinase
      PH
      pleckstrin homology
      MEK
      MAPK/ERK kinase
      The insulin signaling system plays an important role in many physiological processes, including carbohydrate and fat metabolism, reproduction, cellular growth, and survival (
      • White M.F.
      • Myers M.G.
      ). Acute insulin resistance is mediated, at least in part, by the action of pro-inflammatory cytokines that are produced during infection, physical trauma, or cancer (
      • Loddick S.A.
      • Rothwell N.J.
      ,
      • Hotamisligil G.S.
      • Peraldi P.
      • Budvari A.
      • Ellis R.W.
      • White M.F.
      • Spiegelman B.M.
      ,
      • Yoshikawa T.
      • Noguchi Y.
      • Satoh S.
      ). Chronic insulin resistance is an inevitable consequence of genetic variation that is exacerbated by aging and obesity and contributes to multiple disorders, including glucose intolerance, hyperlipidemia, hypertension and cardiovascular mortality, infertility and polycystic ovarian syndrome, and type II diabetes (
      • Maezono K.
      • Osman A.
      • Patti M.E.
      • Cusi K.
      • Pendergrass M.
      • DeFronzo R.A.
      • Mandarino L.
      ,
      • Kahn B.B.
      • Flier J.S.
      ). Insulin resistance alone might not cause diabetes if pancreatic β-cells secrete enough insulin to compensate for reduced sensitivity; however, type II diabetes eventually develops, possibly because hyperinsulinemia itself exacerbates the pre-existing resistance until β-cells eventually fail to compensate (
      • Kahn B.B.
      ). Understanding the molecular basis of insulin resistance will provide a rational basis for treatment of many related disorders.
      The insulin signaling system is complex, and a common mechanism to explain the occurrence of acute and chronic insulin resistance is difficult to identify. Mutations in the insulin receptor are an obvious source of lifelong insulin resistance, but they occur rarely and are not the common cause of type II diabetes (
      • Hani E.H.
      • Suaud L.
      • Boutin P.
      • Chevre J.C.
      • Durand E.
      • Philippi A.
      • Demenais F.
      • Vionnet N.
      • Furuta H.
      • Velho G.
      • Bell G.I.
      • Laine B.
      • Froguel P.
      ,
      • Carboni J.M.
      • Yan N.
      • Cox A.D.
      • Bustelo X.
      • Graham S.M.
      • Lynch M.J.
      • Weinmann R.
      • Seizinger B.R.
      • Der C.J.
      • Barbacid M.
      • Manne V.
      ,
      • Vaxillaire M.
      • Rouard M.
      • Yamagata K.
      • Oda N.
      • Kaisaki P.J.
      • Boriraj V.V.
      • Chevre J.C.
      • Boccio V.
      • Cox R.D.
      • Lathrop G.M.
      • Dussoix P.
      • Philippe J.
      • Timsit J.
      • Charpentier G.
      • Velho G.
      • Bell G.I.
      • Froguel P.
      ,
      • Comb D.G.
      • Roseman S.
      ). Generally, insulin resistance is a consequence of dysregulated insulin signaling that arises from various sources. Nonspecific or regulated degradation of elements in the insulin signaling pathway might cause insulin resistance (
      • Sun X.J.
      • Goldberg J.L.
      • Qiao L.Y.
      • Mitchell J.J.
      ); elevated activity or expression of protein or lipid phosphatases, including PTP1B, SHIP2, and pTen, directly inhibits insulin signals (
      • Ishihara H.
      • Sasaoka T.
      • Hori H.
      • Wada T.
      • Hirai H.
      • Haruta T.
      • Langlois W.J.
      • Kobayashi M.
      ,
      • Clement S.
      • Krause U.
      • Desmedt F.
      • Tanti J.-F.
      • Behrends J.
      • Pesesse X.
      • Sasaki T.
      • Penninger J.
      • Doherty M.
      • Malaisse W.
      • Dumont J.E.
      • Le Maechand-Brustel Y.
      • Erneux C.
      • Hue L.
      • Schurmans S.
      ). Covalent modification of the IRS1 proteins by serine phosphorylation is implicated in insulin resistance associated with obesity and trauma. Serine phosphorylation of IRS-1 is known to be promoted by elevated circulating levels of several metabolites, including free fatty acids, diacylglycerol, fatty acyl-CoAs, ceramides, and glucose (
      • Shulman G.I.
      ). Moreover, adipose-derived cytokines like TNF-α also stimulate serine/threonine phosphorylation of IRS-1, which inhibits signaling (
      • Peraldi P.
      • Hotamisligil G.S.
      • Buurman W.A.
      • White M.F.
      • Spiegelman B.M.
      ).
      One of the branches of the TNF-α signaling pathway involves activation of JNK (
      • Yuasa T.
      • Ohno S.
      • Kehrl J.H.
      • Kyriakis J.M.
      ,
      • Kuan C.Y.
      • Yang D.D.
      • Samanta Roy D.R.
      • Davis R.J.
      • Rakic P.
      • Flavell R.A.
      ,
      • Rincon M.
      • Whitmarsh A.
      • Yang D.D.
      • Weiss L.
      • Derijard B.
      • Jayaraj P.
      • Davis R.J.
      • Flavell R.A.
      ). JNK phosphorylates numerous cellular proteins, including IRS-1, IRS-2, Shc, and Gab-1 (
      • Aguirre V.
      • Uchida T.
      • Yenush L.
      • Davis R.J.
      • White M.F.
      ). Previous work has revealed that the major JNK phosphorylation site in rat IRS-1 is located at Ser307 (Ser312 in human IRS-1), which is located on the C-terminal side of the phosphotyrosine-binding (PTB) domain (
      • Aguirre V.
      • Uchida T.
      • Yenush L.
      • Davis R.J.
      • White M.F.
      ). In this report, a yeast tri-hybrid assay revealed that JNK1 phosphorylation of Ser307 inhibits the interaction between IRS-1 and the insulin receptor, providing a rational mechanism to explain, at least in part, the insulin resistance that occurs during trauma and obesity.

      DISCUSSION

      Our results reveal a general mechanism for the negative feedback and heterologous regulation of the IRS-1 branch of the insulin signaling pathway through inhibition of PTB domain function by phosphorylation of Ser307. Previous work established that the interaction in yeast between the insulin receptor catalytic domain and IRS-1 is mediated entirely through the binding of the phosphorylated NPEY motif in the insulin receptor to the PTB domain in IRS-1 (
      • Craparo A.
      • O'Neill T.J.
      • Gustafson T.A.
      ,
      • O'Neill T.J.
      • Craparo A.
      • Gustafson T.A.
      ,
      • Gustafson T.A.
      • He W.
      • Craparo A.
      • Schaub C.D.
      • O'Neill T.J.
      ). Based on this prior information, we conclude that disruption of the binding between the insulin receptor and IRS-1 in yeast expressing JNK1 occurs because phosphorylation of Ser307 disrupts PTB domain function (
      • Wolf G.
      • Trub T.
      • Ottinger E.
      • Groninga L.
      • Lynch A.
      • White M.F.
      • Miyazaki M.
      • Lee J.
      • Shoelson S.E.
      ,
      • Yenush L.
      • Makati K.J.
      • Smith-Hall J.
      • Ishibashi O.
      • Myers Jr., M.G.
      • White M.F.
      ). All of the control experiments confirmed this conclusion, including association of the insulin receptor and IRS-1 in yeast expressing a kinase-dead JNK1 construct, association of the insulin receptor and a human IRS-1 mutant (Ser312 → Ala) in yeast expressing a functional JNK1 construct, and association of the insulin receptor and an IRS-1 construct lacking the JIP homology region in yeast expressing JNK1.
      Although the yeast tri-hybrid assay reveals that Ser307phosphorylation completely abrogates insulin receptor/IRS-1 interaction, the 32DIR cell-based experiments suggest that it inhibits IRS-1 tyrosine phosphorylation by only 50% at best. Previous work revealed that efficient phosphorylation of IRS-1 depends on two N-terminal domains, the pleckstrin homology (PH) domain and the adjacent PTB domain (
      • Yenush L.
      • Makati K.J.
      • Smith-Hall J.
      • Ishibashi O.
      • Myers Jr., M.G.
      • White M.F.
      ,
      • Burks D.J.
      • Pons S.
      • Towery H.
      • Smith-Hall J.
      • Myers Jr., M.G.
      • Yenush L.
      • White M.F.
      ). Deletion of both the PH and PTB domains completely inhibits phosphorylation during insulin stimulation of 32DIR cells, whereas deletion of either the PH or PTB domain partially reduces tyrosine phosphorylation. Since Ser307 phosphorylation inhibits PTB domain function, persistent coupling mediated through the PH domain might be responsible for incomplete inhibition of IRS-1 tyrosine phosphorylation. Efficient coupling of IRS-1 to low levels of insulin receptors requires both domains, whereas either the PH or PTB domain is sufficient in cells expressing high levels of insulin receptor. Therefore, in cells with a low number of receptors, Ser307 phosphorylation might play a major regulatory role, whereas Ser307 phosphorylation might be inefficient in cells with a high number of receptors (
      • Yenush L.
      • Makati K.J.
      • Smith-Hall J.
      • Ishibashi O.
      • Myers Jr., M.G.
      • White M.F.
      ). Under the latter condition, more drastic regulatory mechanisms might be required, including degradation of IRS-1.
      Considerable evidence is largely consistent with the hypothesis that serine phosphorylation of the insulin receptor or the IRS proteins inhibits signal transduction. Despite the potential importance of this regulatory pathway, the sites of phosphorylation and the inhibitory mechanisms involved have been difficult to identify. Increased serine phosphorylation of IRS-1 is a common finding in insulin resistance and type II diabetes (
      • Virkamaki A.
      • Ueki K.
      • Kahn C.R.
      ). Serine-phosphorylated IRS-1 inhibits insulin-stimulated autophosphorylation of the insulin receptor, PI3K activation, glucose uptake, and other insulin-stimulated biological responses (
      • Hotamisligil G.S.
      • Peraldi P.
      • Budvari A.
      • Ellis R.W.
      • White M.F.
      • Spiegelman B.M.
      ,
      • De Fea K.
      • Roth R.A.
      ,
      • Chin J.E.
      • Liu F.
      • Roth R.A.
      ,
      • De Li J.
      • Fea K.
      • Roth R.A.
      ,
      • Mothe I.
      • Van Obberghen E.
      ,
      • Tanti J.-F.
      • Gremeaux T.
      • Van Obberghen E.
      • Le Marchand-Brustel Y.
      ,
      • De Meyts P.
      ,
      • Richardson J.M.
      • Pessin J.E.
      ,
      • Kroder G.
      • Beossenmaier B.
      • Kellerer M.
      • Capp E.
      • Stoyanov B.
      • Muhlhofer A.
      • Berti L.
      • Horikoshi H.
      • Ullrich A.
      • Haring H.
      ,
      • Paz K.
      • Hemi R.
      • LeRoith D.
      • Karasik A.
      • Elhanany E.
      • Kanety H.
      • Zick Y.
      ). Besides the JNK phosphorylation site at Ser307, IRS-1 contains serine/threonine residues in consensus sequences for many other protein kinases, including casein kinase II, cAMP-dependent protein kinase, protein kinase C, Cdc2 kinase, MAPK, and protein kinase B/Akt (
      • Sun X.J.
      • Wang L.M.
      • Zhang Y.
      • Yenush L.
      • Myers Jr., M.G.
      • Glasheen E.M.
      • Lane W.S.
      • Pierce J.H.
      • White M.F.
      ,
      • De Fea K.
      • Roth R.A.
      ,
      • De Li J.
      • Fea K.
      • Roth R.A.
      ,
      • Sun X.J.
      • Rothenberg P.L.
      • Kahn C.R.
      • Backer J.M.
      • Araki E.
      • Wilden P.A.
      • Cahill D.A.
      • Goldstein B.J.
      • White M.F.
      ,
      • Barthel A.
      • Nakatani K.
      • Dandekar A.A.
      • Roth R.A.
      ,
      • De Fea K.
      • Roth R.A.
      ). Recent reports suggest that serine phosphorylation of IRS-1 inhibits its ability to associate with the insulin receptor and to serve as a substrate for tyrosine phosphorylation (
      • Hotamisligil G.S.
      • Peraldi P.
      • Budvari A.
      • Ellis R.W.
      • White M.F.
      • Spiegelman B.M.
      ,
      • De Fea K.
      • Roth R.A.
      ,
      • Mothe I.
      • Van Obberghen E.
      ,
      • Paz K.
      • Hemi R.
      • LeRoith D.
      • Karasik A.
      • Elhanany E.
      • Kanety H.
      • Zick Y.
      ,
      • De Fea K.
      • Roth R.A.
      ,
      • Kanety H.
      • Feinstein R.
      • Papa M.Z.
      • Hemi R.
      • Karasik A.
      ). Thus, the identification of serine/threonine phosphorylation-based mechanisms of signal inhibition might reveal a molecular basis for insulin resistance that promotes the pathogenesis of type II diabetes.
      Ser307 phosphorylation promotes general inhibition of IRS-1 signaling, as revealed by reduced activation of both the PI3K and MAPK cascades. This effect does not occur through inhibition of insulin receptor autophosphorylation, but is consistent with reduced coupling between the insulin receptor and IRS-1. Association of p85 or Grb2 with IRS-1 depends on distinct sets of tyrosine phosphorylation motifs that are separated by up to 300 amino acids in the primary sequence. These results are consistent with the general inhibition of tyrosine phosphorylation expected during inhibition of PTB domain function by Ser307 phosphorylation. This general inhibition is in contrast to the specific inhibition of p85 association at tyrosine phosphorylation motifs directly adjacent to previously identified inhibitory serine residues (
      • Delahaye L.
      • Mothe-Satney I.
      • Myers Jr., M.G.
      • White M.F.
      • Van Obberghen E.
      ,
      • Mothe I.
      • Van Obberghen E.
      ,
      • De Fea K.
      • Roth R.A.
      ).
      At least three kinases apparently mediate phosphorylation of Ser307, including a TNF-α/anisomycin-stimulated kinase other than JNK and an insulin/IGF-1-stimulated kinase that is inhibited by wortmannin/LY294002 and requires PI3K activity. We originally thought that JNK might be the common final step that mediates Ser307 phosphorylation downstream of various cytokines, an especially attractive hypothesis since JNK1 binds to IRS-1 (
      • Aguirre V.
      • Uchida T.
      • Yenush L.
      • Davis R.J.
      • White M.F.
      ) and since the JNK-binding region of IRS-1 is required for the inhibition of insulin-stimulated tyrosine phosphorylation of IRS-1 by anisomycin. However, some experiments with potential physiological mediators of insulin resistance do not support this hypothesis. Whereas anisomycin and TNF-α stimulate JNK and Ser307 phosphorylation, the MEK kinase inhibitor PD98059 completely inhibits Ser307phosphorylation, with no effect on JNK activity (
      • Rui L.
      • Aguirre V.
      • Kim J.K.
      • Shulman G.I.
      • Lee A.
      • Corbould A.
      • Dunaif A.
      • White M.F.
      ). Although insulin activates JNK in certain cells, this pathway is not inhibited by wortmannin/LY294002, suggesting that a distinct cascade is involved. Therefore, in addition to JNK, at least two other kinases apparently mediate phosphorylation of Ser307. These kinases might possess the common ability to bind to the JNK-binding domain in IRS-1, although other mechanisms could be involved.
      In summary, potential mediators of chronic insulin resistance, such as TNF-α and hyperinsulinemia, lead to progressive accumulation of IRS-1 molecules that are phosphorylated at Ser307 and that couple less efficiently to the insulin receptor. Chronic Ser307phosphorylation might also target IRS-1 for degradation or to subcellular compartments inaccessible to the activated insulin receptor. Other IRS proteins, especially IRS-2, might be similarly sensitive to serine phosphorylation. IRS-2 contains a JIP homology region, although a residue analogous to Ser307 does not exist in IRS-2 (
      • Aguirre V.
      • Uchida T.
      • Yenush L.
      • Davis R.J.
      • White M.F.
      ). Nevertheless, IRS-2 is serine-phosphorylated during TNF-α or anisomycin stimulation, which inhibits insulin-stimulated tyrosine phosphorylation. Since IRS-1 is essential to sustain compensatory insulin secretion in mice, serine phosphorylation-mediated inhibition might promote both peripheral insulin resistance and β-cell failure. Identification of the phosphorylation sites in IRS-2 that inhibit insulin-stimulated tyrosine phosphorylation and the kinase specific to those sites is an important target for future mechanism-based drug discovery.

      Acknowledgments

      We thank Lauren Kelly for excellent secretarial assistance, Liangyou Rui for technical assistance and critical review, and Jeff Thomas for technical assistance.

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