Translation Insulin regulation of translation
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 controlledby Insulin.
Insulin binds to Iinsulin receptors and rapidly activates proteinsynthesis by activating components of the translational system, including eIFs(eukaryotic initiation factors) and eEFs (eukaryotic elongation factors) [1].
The activation of protein synthesis by Insulin is mediated primarily throughPhosphoinositide 3-kinase ( PI3K ). This involves the activation of v-akt murinethymoma viral oncogene homolog 1 ( AKT(PKB) ) where AKT(PKB) phosphorylatesand inactivates Glycogen synthase kinase 3 beta ( GSK3 beta ), which in turnphosphorylates and inhibits subunit of eIF2B complex - Eukaryotic translationinitiation factor 2B, subunit 5 epsilon, 82kDa ( eIF2B5 ). Initiation factoreIF2B 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, whichbinds to the 40S ribosomal subunit. eIF2B acts by promoting the release of GDPfrom eIF2, thus allowing it to be replaced by GTP, to regenerate the activeeIF2-GTP complex. Since eIF2 is required for every initiation event,modulating the activity of eIF2B provides a mechanism for controlling overallrates of peptide-chain initiation [2], [3].
AKT(PKB) also phosphorylates and inhibits the Tuberous sclerosis 1(Hamartin )- Tuberous sclerosis 2 ( Tuberin ) complex to relieve itsinhibitory action on the FK506 binding protein 12-rapamycin associated protein 1 (mTOR ). Upon Insulin stimulation, mTOR phosphorylates Eukaryotictranslation initiation factor 4E binding protein 1 ( 4E-BP1 ) leading to theformation of an active eIF-4F complex . The eIF4F complex iscomposed of Eukaryotic translation initiation factor 4E ( eIF4E ), the cap-bindingprotein, eukaryotic translation initiation factor 4 gamma, 1 -3 ( eIF4G1/3 ), alarge polypeptide with binding sites for a number of other proteins, includingeIF4E, and an ATP-dependent RNA-helicase Eukaryotic translation initiation factor4A ( eIF4A ).
The principal mechanism utilized in the regulation of eIF4E activity is throughits interaction with a family of binding/repressor proteins termed 4E-BP1. Thebinding of 4E-BP1 to eIF4E prevents the interaction of eIF4E witheIF4G1/3 which then suppresses the formation of the eIF-4F complex. Theability of 4E-BP1 to interact with eIF4E is controlled via thephosphorylation of 4E-BP1 [4].
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 theribosome moves relative to the mRNA and the peptidyl-tRNA migrates from the A- to theP-site of the ribosome [1].
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