Regulation of lipid metabolism - Insulin signaling:generic cascades

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Insulin signaling: generic cascades

The binding of Insulin to the extracellular domain of the Insulin receptor results in the activation of the tyrosine kinase activity of the receptor. Following the autophosphorylation, the Insulin receptor phosphorylates a number of intracellular substrates to initiate a series of intracellular signaling pathways. These substrates include Insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and SHC (Src homology 2 domain containing) transforming protein 1 (Shc). The Phosphotyrosine residues in both IRS-1, IRS-2 and Shc act as docking sites for other proteins which contain Src-homology 2 (SH2) domains. The two most important are Growth factor receptor bound 2 (Grb2) and the Phosphatidylinositol 3-kinase, regulatory (PI3K reg class IA), which lead to the activation of Harvey rat sarcoma viral oncogene homolog (H-Ras)/ Mitogen-activated protein kinase 1-3 (ERK1/2) and PI3-kinase pathways, respectively [1], [2], [3].

Son of sevenless homolog (Sos) is a guanine nucleotide exchange factor (GEF) that promotes the exchange of GDP on Ras with GTP, yielding the active form of H-Ras. In response to Insulin, adaptor protein GRB-2 binds to SOS. GRB-2 - SOS complex is able to binds to phosphorylated IRS-1, IRS-2 or Shc. This binding is thought to bring the GRB-2-SOS complex to the plasma membrane in the vicinity of H-Ras [4].

Activated H-Ras initiates v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2))/ Mitogen-activated protein kinase 1-3 (ERK1/2) cascade that results in the stimulation of Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1) [5], [6]. This signaling cascade modulates activity of Eukaryotic elongation factor-2 kinase (eEF2K) via Eukaryotic translation elongation factor 2 (eEF2) activation and regulates translation at the elongation process.

PI3K is activated when its regulator subunit PI3K reg class IA becomes bound to IRS-1 or IRS-2, resulting in an increase in the product PtdIns(3,4,5)P3 [7], [8].

The activation of PI3K appears to be necessary for many of the effects of Insulin, including the protein kinase cascades involving 3-phosphoinositide dependent protein kinase-1 PDK1(PDPK1), v-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) and Ribosomal protein S6 kinase, 70kDa, polypeptides 1 and 2 (p70 S6K1 and p70 S6K2). PtdIns(3,4,5)P3 is able to exert a dual effect on AKT(PKB) activation involves both direct binding and activation of AKT(PKB) and stimulation of the upstream kinase PDK1(PDPK1) and subsequently phosphorylation and activation of AKT(PKB) [9].

AKT(PKB) is able to phosphorylate Glycogen synthase kinase 3 beta (GSK3 beta), thereby decreasing the activity of this kinase. As a consequence, AKT(PKB) abolishes the inhibition of glycogen synthesis and activates translation via the regulatory activity of initiation factor of translation Eukaryotic translation initiation factor 2 (eIF2). AKT(PKB) also phosphorylates and inhibits the Tuberous sclerosis 1 (Hamartin)- Tuberous sclerosis 2 (Tuberin) complex to relieve its inhibitory action on the FK506 binding protein 12-rapamycin associated protein 1 (mTOR), which phosphorylates Eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and this event allow to formed active eIF-4F complex for initiation translation [10]. Activation of mTOR pathway by Insulin suppresses autophagy [11].

AKT(PKB) is also involved in regulating fatty acid synthesis and lipolysis. AKT directly activates key enzymes in fatty acid synthesis - ATP citrate lyase (ACLY) and inhibits of key enzyme in lipolysis - Lipase, hormone-sensitive (LIPS). Insulin induced AKT(PKB) activity also leads to glucose transporter mobilization and glucose uptake in several tissues.[12], [13].

References:

  1. Pronk GJ, McGlade J, Pelicci G, Pawson T, Bos JL
    Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. The Journal of biological chemistry 1993 Mar 15;268(8):5748-53
  2. Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D
    Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. The Journal of clinical investigation 2000 Jan;105(2):199-205
  3. Murata H, Hresko RC, Mueckler M
    Reconstitution of phosphoinositide 3-kinase-dependent insulin signaling in a cell-free system. The Journal of biological chemistry 2003 Jun 13;278(24):21607-14
  4. Ehrhardt A, Ehrhardt GR, Guo X, Schrader JW
    Ras and relatives--job sharing and networking keep an old family together. Experimental hematology 2002 Oct;30(10):1089-106
  5. Rodriguez-Viciana P, Sabatier C, McCormick F
    Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Molecular and cellular biology 2004 Jun;24(11):4943-54
  6. Eblen ST, Kumar NV, Shah K, Henderson MJ, Watts CK, Shokat KM, Weber MJ
    Identification of novel ERK2 substrates through use of an engineered kinase and ATP analogs. The Journal of biological chemistry 2003 Apr 25;278(17):14926-35
  7. Funaki M, Katagiri H, Inukai K, Kikuchi M, Asano T
    Structure and function of phosphatidylinositol-3,4 kinase. Cellular signalling 2000 Mar;12(3):135-42
  8. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  9. Zou W, Li ZY, Li CL, Cui ZC
    [Protein kinase B and its role in the signal transduction pathway mediated by phosphoinositide 3-kinase]. Sheng li ke xue jin zhan [Progress in physiology] 2000 Apr;31(2):120-4
  10. Proud CG
    Regulation of protein synthesis by insulin. Biochemical Society transactions 2006 Apr;34(Pt 2):213-6
  11. Kanazawa T, Taneike I, Akaishi R, Yoshizawa F, Furuya N, Fujimura S, Kadowaki M
    Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. The Journal of biological chemistry 2004 Feb 27;279(9):8452-9
  12. Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM
    The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. The Journal of biological chemistry 2002 Sep 13;277(37):33895-900
  13. Wang J, Shen WJ, Patel S, Harada K, Kraemer FB
    Mutational analysis of the "regulatory module" of hormone-sensitive lipase. Biochemistry 2005 Feb 15;44(6):1953-9

  1. Pronk GJ, McGlade J, Pelicci G, Pawson T, Bos JL
    Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. The Journal of biological chemistry 1993 Mar 15;268(8):5748-53
  2. Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D
    Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. The Journal of clinical investigation 2000 Jan;105(2):199-205
  3. Murata H, Hresko RC, Mueckler M
    Reconstitution of phosphoinositide 3-kinase-dependent insulin signaling in a cell-free system. The Journal of biological chemistry 2003 Jun 13;278(24):21607-14
  4. Ehrhardt A, Ehrhardt GR, Guo X, Schrader JW
    Ras and relatives--job sharing and networking keep an old family together. Experimental hematology 2002 Oct;30(10):1089-106
  5. Rodriguez-Viciana P, Sabatier C, McCormick F
    Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Molecular and cellular biology 2004 Jun;24(11):4943-54
  6. Eblen ST, Kumar NV, Shah K, Henderson MJ, Watts CK, Shokat KM, Weber MJ
    Identification of novel ERK2 substrates through use of an engineered kinase and ATP analogs. The Journal of biological chemistry 2003 Apr 25;278(17):14926-35
  7. Funaki M, Katagiri H, Inukai K, Kikuchi M, Asano T
    Structure and function of phosphatidylinositol-3,4 kinase. Cellular signalling 2000 Mar;12(3):135-42
  8. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  9. Zou W, Li ZY, Li CL, Cui ZC
    [Protein kinase B and its role in the signal transduction pathway mediated by phosphoinositide 3-kinase]. Sheng li ke xue jin zhan [Progress in physiology] 2000 Apr;31(2):120-4
  10. Proud CG
    Regulation of protein synthesis by insulin. Biochemical Society transactions 2006 Apr;34(Pt 2):213-6
  11. Kanazawa T, Taneike I, Akaishi R, Yoshizawa F, Furuya N, Fujimura S, Kadowaki M
    Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. The Journal of biological chemistry 2004 Feb 27;279(9):8452-9
  12. Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM
    The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. The Journal of biological chemistry 2002 Sep 13;277(37):33895-900
  13. Wang J, Shen WJ, Patel S, Harada K, Kraemer FB
    Mutational analysis of the "regulatory module" of hormone-sensitive lipase. Biochemistry 2005 Feb 15;44(6):1953-9

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