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) [1].
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 [2], [3].
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 [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 the ribosome moves relative to the mRNA and the peptidyl-tRNA migrates from
the A- to the P-site of the ribosome [1].
References:
- Proud CG
Regulation of protein synthesis by insulin.
Biochemical Society transactions 2006 Apr;34(Pt 2):213-6
- Welsh GI, Miller CM, Loughlin AJ, Price NT, Proud CG
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
- Proud CG
eIF2 and the control of cell physiology.
Seminars in cell & developmental biology 2005 Feb;16(1):3-12
- Gingras AC, Raught B, Sonenberg N
eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.
Annual review of biochemistry 1999;68:913-63
