Pathway Map Details
Translation_Insulin regulation of translation
Object list (links open in MetaCore):
PDK (PDPK1), 22.214.171.124, eIF4B, Shc, PtdIns(4,5)P2, eIF2B, eIF2, Insulin, PI3K cat class IA, PKC-zeta, eIF4G1/3, Hamartin, eEF2K, SOS, PP1-cat, eEF2, ERK1/2, mTOR, Tuberin, eIF2B5, GRB2, IRS-1, GSK3 beta, RPS6, MEK2(MAP2K2), RHEB2, p70 S6 kinase1, IRS-2, c-Raf-1, mRNA, eIF4E, 4E-BP1, H-Ras, eIF4H, AKT (PKB), p90RSK1, p70 S6 kinase2, eIF4A, MEK1(MAP2K1), Insulin receptor, PI3K reg class IA, PtdIns(3,4,5)P3
Insulin regulation of translation.
Insulin plays an important role in the overall regulation of protein synthesis. Protein synthesis (mRNA translation) is conventionally divided into three stages: initiation, elongation and termination. Both initiation and elongation can be controlled by Insulin.
Insulin binds to Iinsulin receptors and rapidly activates protein synthesis by activating components of the translational system, including eIFs (eukaryotic initiation factors) and eEFs (eukaryotic elongation factors) .
The activation of protein synthesis by Insulin is mediated primarily through Phosphoinositide 3-kinase ( PI3K ). This involves the activation of v-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) where AKT(PKB) phosphorylates and inactivates Glycogen synthase kinase 3 beta ( GSK3 beta ), which in turn phosphorylates and inhibits subunit of eIF2B complex - Eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa ( eIF2B5 ). Initiation factor eIF2B mediates the recycling of Eukaryotic translation initiation factor 2 ( eIF2 ); a major player in recruiting of the initiator Met-tRNA to the ribosome. eIF2 is active when bound with GTP and forms a eIF2-GTP-Met-tRNA complex, which binds to the 40S ribosomal subunit. eIF2B acts by promoting the release of GDP from eIF2, thus allowing it to be replaced by GTP, to regenerate the active eIF2-GTP complex. Since eIF2 is required for every initiation event, modulating the activity of eIF2B provides a mechanism for controlling overall rates of peptide-chain initiation , .
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 ). Upon Insulin stimulation, mTOR phosphorylates Eukaryotic translation initiation factor 4E binding protein 1 ( 4E-BP1 ) leading to the formation of an active eIF-4F complex . The eIF4F complex is composed of Eukaryotic translation initiation factor 4E ( eIF4E ), the cap-binding protein, eukaryotic translation initiation factor 4 gamma, 1 -3 ( eIF4G1/3 ), a large polypeptide with binding sites for a number of other proteins, including eIF4E, and an ATP-dependent RNA-helicase Eukaryotic translation initiation factor 4A ( eIF4A ).
The principal mechanism utilized in the regulation of eIF4E activity is through its interaction with a family of binding/repressor proteins termed 4E-BP1. The binding of 4E-BP1 to eIF4E prevents the interaction of eIF4E with eIF4G1/3 which then suppresses the formation of the eIF-4F complex. The ability of 4E-BP1 to interact with eIF4E is controlled via the phosphorylation of 4E-BP1 .
Insulin induces activation of Eukaryotic translation elongation factor 2 ( eEF2 ) to accelerate elongation. Insulin inhibits Eukaryotic elongation factor-2 kinase ( eEF2K ) via v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/ Mitogen-activated protein kinase 1-3 ( ERK1/2 ) and/or PI3K/ AKT(PKB) pathways and abolish inhibitory action eEF2K on eEF2. eEF2 is required for the translocation step of elongation during which the ribosome moves relative to the mRNA and the peptidyl-tRNA migrates from the A- to the P-site of the ribosome .
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Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS letters 1998 Jan 9;421(2):125-30
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eIF2 and the control of cell physiology. Seminars in cell & developmental biology 2005 Feb;16(1):3-12
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eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annual review of biochemistry 1999;68:913-63