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Regulation of lipid metabolism Insulin signaling:generic cascades


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Regulation of lipid metabolism Insulin signaling:generic cascades

Insulin signaling: generic cascades

The binding of Insulin to the extracellular domain of the Insulinreceptor results in the activation of the tyrosine kinase activity of the receptor.Following the autophosphorylation, the Insulin receptor phosphorylates a number ofintracellular substrates to initiate a series of intracellular signaling pathways. Thesesubstrates 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 asdocking sites for other proteins which contain Src-homology 2 (SH2) domains. The two mostimportant are Growth factor receptor bound 2 ( Grb2 ) and the Phosphatidylinositol3-kinase, regulatory ( PI3K reg class IA ), which lead to the activation of Harveyrat 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 ofH-Ras. In response to Insulin, adaptor protein GRB-2 binds toSOS. 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 tothe 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 thatresults in the stimulation of Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1 ) [5], [6]. This signaling cascade modulatesactivity of Eukaryotic elongation factor-2 kinase ( eEF2K ) via Eukaryotictranslation elongation factor 2 ( eEF2 ) activation and regulates translation atthe elongation process.

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

The activation of PI3K appears to be necessary for many of the effects ofInsulin, including the protein kinase cascades involving 3-phosphoinositidedependent protein kinase-1 PDK1(PDPK1), v-akt murine thymoma viral oncogenehomolog 1 ( AKT(PKB) ) and Ribosomal protein S6 kinase, 70kDa, polypeptides 1 and2 ( p70 S6K1 and p70 S6K2 ). PtdIns(3,4,5)P3 is able to exert a dualeffect on AKT(PKB) activation involves both direct binding and activation ofAKT(PKB) and stimulation of the upstream kinase PDK1(PDPK1) andsubsequently phosphorylation and activation of AKT(PKB) [9].

AKT(PKB) is able to phosphorylate Glycogen synthase kinase 3 beta ( GSK3beta ), thereby decreasing the activity of this kinase. As a consequence,AKT(PKB) abolishes the inhibition of glycogen synthesis and activates translationvia the regulatory activity of initiation factor of translation Eukaryotic translationinitiation factor 2 ( eIF2 ). AKT(PKB) also phosphorylates and inhibits theTuberous sclerosis 1 (Hamartin )- Tuberous sclerosis 2 ( Tuberin ) complexto relieve its inhibitory action on the FK506 binding protein 12-rapamycin associatedprotein 1 ( mTOR ), which phosphorylates Eukaryotic translation initiation factor4E binding protein 1 ( 4E-BP1 ) and this event allow to formed activeeIF-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 glucosetransporter mobilization and glucose uptake in several tissues.[11], [12].