Pathway Map Details

Regulation of lipid metabolism_Insulin signaling:generic cascades



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GSK3 beta, LIPS, PDE3B, eIF2B5, RHEB2, 4E-BP1, p90RSK1, PKC-zeta, AMP, 3.1.4.17, eIF4B, RPS6, PI3K cat class IA, PtdIns(4,5)P2, PKA-cat (cAMP-dependent), Shc, Erk (MAPK1/3), Insulin, PP1G regulatory subunit, IPP-1, c-Raf-1, PtdIns(3,4,5)P3, H-Ras, PDK (PDPK1), IRS-2, p70 S6 kinase1, AKT(PKB), Tuberin, PDHA (somatic), GLUT4, GRB2, eEF2K, ACLY, SOS, MEK1(MAP2K1), mTOR, MEK2(MAP2K2), eEF2, p70 S6 kinase2, PI3K reg class IA, PP1-cat, Insulin receptor, PKA-reg (cAMP-dependent), IRS-1, 2.7.1.153, AKT2, Cyclic AMP cytosol

Description:

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].

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. [11], [12].

References:

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    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
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    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
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    Ras and relatives--job sharing and networking keep an old family together. Experimental hematology 2002 Oct;30(10):1089-106
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  8. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
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  9. Zou W, Li ZY, Li CL, Cui ZC
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  10. Proud CG
    Regulation of protein synthesis by insulin. Biochemical Society transactions 2006 Apr;34(Pt 2):213-6
  11. 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
  12. 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