Regulation of eIF4 activity
Protein biosynthesis is largely governed by a cohort of Eukaryotic translation
initiation factors (eIF) that mediate specific steps in the
initiation process. A rate-limiting step in translation
initiation involves formation of the eIF4F complex that
recruits ribosomal subunits to mRNA, a process known as cap-dependent translation .
eIF4F complex consists of Eukaryotic translation
initiation factor 4 gamma, factor 4E and factor 4A (eIF4G,
eIF4G serves as a scaffold protein for the assembly of
eIF4E and eIF4A. There are two
functional homologs of mammalian eIF4G, termed
eIF4G1 and eIF4G3, which share
46% identical and have similar biochemical activities .
eIF4A is an ATP-dependent DEAD-box RNA helicase that
functions in translation initiation to catalyze the unwinding of mRNA secondary structure
at the 5'UTR. The RNA helicase activity of eIF4A is enhanced
by eIF4B or eIF4H binding.
eIF4A is most active as a helicase when it is a subunit of
eIF4E is a eukaryotic translation initiation factor that
is involved in directing ribosomes to the cap structure of mRNAs.
eIF4E is an important modulator of cell growth and
proliferation. eIF4E is the least abundant of all initiation
factors, and under most circumstances is considered to be the rate-limiting factor in the
binding of ribosomes to the mRNA. Consequently, eIF4E is a
major target for regulation .
Two main pathways have been characterized that regulate
The first pathway emanates from Phosphatidylinositol 3-kinase
(PI3K), and influences both
eIF4E and eIF4A activity. It is
activated by several stimuli, including hormones, growth factors and cytokines. For
example, Epidermal growth factor (EGF), when bound with its
receptor (EGFR), stimulates enzymatic activity of
PI3K class IA directly or via Insulin receptor substrate
(IRS-1)  or by SHC transforming protein
(Shc)/Growth factor receptor bound 2
(Grb2)/Son of Sevenless proteins
Activation of PI3K leads to increase of
Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3),
which activates V-akt murine thymoma viral oncogene homolog 1
(AKT) (by membrane recruitment
and phosphorylation by 3-phosphoinositide dependent protein kinase
(PDK)) . AKT
activates Rapamycin associated protein FRAP2 (mTOR) through
Tuberin/GTP-binding protein Ras homolog enriched in brain
(RHEB) pathway .
mTOR phosphorylates and inactivates eIF4E-bindind protein
(4E-BP), a repressor of eIF4E
and mRNA translation. mTOR also activates ribosomal protein
70-kD 6S kinases (p70 S6 kinase1 and p70 S6
kinase2), either directly or indirectly (through Immunoglobulin-binding
protein 1 (IGBP1) and Protein phosphatase 2A
(PP2A). p70 S6
kinases activation is also regulated by its
phosphorylation by protein kinase C zeta type (PKC-zeta)
and/or PDK. p70 S6 kinases
activate co-factor eIF4B .
Another pathway that regulates eIF4 phosphorylation
involves Mitogen-activated protein family kinases, specifically Mitogen-activated protein
kinases Erk and p38.
Erk is activated through the sequential activation of
Ras (via guanosine 5'-triphosphate exchange), proto-oncogen
serine/threonine-protein kinase, c-Raf-1 (via membrane
recruitment and phosphorylation), and then dual specificity MAP kinases
(MEK1 and MEK2).
p38 pathway is involved in the regulation of growth arrest,
apoptosis, and proliferation induced by stress signals (e.g., UV irradiation, heat- or
cold-shock, osmotic stress), cytokines (e.g., Interleukin-1 (IL-1), or Tumor necrosis
factor alpha (TNF-alpha), and by G protein-coupled receptor agonists (e.g., Thrombin)
Extracellular signal may be transferred to MAPK cascade
through either Ras-related C3 botulinum toxin substrate 1
(Rac1) (hormones, growth factors, cytokines) or through Cell
division cycle 42 (CDC42) (chemotactic signals, physical
stress, cell-cell contacts). Further, Rac1 together with
CDC42 activate Mitogen-activated protein kinase kinase
kinases (MAP3Ks) directly (e.g. mitogen-activated protein
kinase kinase kinase 11 (MLK3)) or via p21 protein activated
kinase 1 (PAK1) (e.g. Mitogen-activated protein kinase
kinase kinase 1 (MAP3K1)) .
Some of MAP3Ks are activated by distinct extracellular
stimuli. For example, Mitogen-activated protein kinase kinase kinase 7
(TAK1) is activated by Transforming growth factor beta
(TGF-beta) and cytokines , .
Consequently, MAP3Ks phosphorylate two serine/threonine
residues in the activation/phosphorylation sites of the defined
MAP2Ks, Mitogen-activated protein kinase kinase 3, 4 and
(MEK3, MEK4 and
MEK6), which phosphorylate
p38 mitogen-activated protein kinase isoforms , , . p38, as well as
Erk activates dually regulated MAP kinase-interacting
serine/threonine kinase 1 (MNK1) and Mitogen- and
stress-activated protein kinase (MSK1) , .
eIF4E is modulated by phosphorylation by
MNK1 and via interaction with Eukaryotic translation
initiation factor 4E binding protein 1
Phosphorylation of eIF4E by
MNK1 is regulated by competitive protein binding with
eIF4G1/3 and eIF4G2 .
The eIF4E-binding motif of
4E-BP1 interacts with a region of
eIF4E that also binds to eIF4G.
Therefore, interaction of 4E-BP1 with
eIF4E blocks eIF4F complex
formation by preventing binding of eIF4G to
eIF4E. Phosphorylation of
4E-BP1 by MNK1 and
MSK antagonizes its binding to
eIF4E , . During mitogenic
conditions, nutrient surplus, and early adenovirus infection,
4E-BP1 becomes phosphorylated and dissociates from
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