Translation Regulation activity of EIF4F
Regulation of eIF4 Protein biosynthesis is largely governed by a cohort of Eukaryotic translationinitiation factors ( eIF ) that mediate specific steps in the initiation process. A rate-limiting step in translation initiation involvesformation of the eIF4F complex that recruits ribosomal subunits to mRNA, a processknown as cap-dependent translation . eIF4F complex consists of Eukaryotic translation initiation factor 4 gamma,factor 4E and factor 4A ( eIF4G, eIF4E, eIF4A ). eIF4G serves as ascaffold protein for the assembly of eIF4E and eIF4A. There are twofunctional 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 translationinitiation to catalyze the unwinding of mRNA secondary structure at the 5'UTR. The RNAhelicase activity of eIF4A is enhanced by eIF4B or eIF4H binding.eIF4A is most active as a helicase when it is a subunit of eIF4F . eIF4E is a eukaryotic translation initiation factor that is involved indirecting ribosomes to the cap structure of mRNAs. eIF4E is an important modulatorof cell growth and proliferation. eIF4E is the least abundant of all initiationfactors, and under most circumstances is considered to be the rate-limiting factor in thebinding of ribosomes to the mRNA. Consequently, eIF4E is a major target forregulation . Two main pathways have been characterized that regulate eIF4Fphosphorylation. The first pathway emanates from Phosphatidylinositol 3-kinase ( PI3K ), andinfluences both eIF4E and eIF4A activity. It is activated by severalstimuli, including hormones, growth factors and cytokines. For example, Epidermal growthfactor ( EGF ), when bound with its receptor ( EGFR ), stimulates enzymaticactivity of PI3K class IA directly or via Insulin receptor substrate (IRS-1 )  or by SHC transforming protein ( Shc )/Growthfactor receptor bound 2 ( Grb2 )/Son of Sevenless proteins ( SOS)/Transforming proteins ( Ras ) pathway. 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-phosphoinositidedependent protein kinase ( PDK )) . AKT activates Rapamycinassociated protein FRAP2 ( mTOR ) through Tuberin/GTP-binding protein Rashomolog enriched in brain ( RHEB ) pathway . mTORphosphorylates and inactivates eIF4E-bindind protein ( 4E-BP ), a repressor ofeIF4E and mRNA translation. mTOR also activates ribosomal protein 70-kD 6Skinases ( p70 S6 kinase1 and p70 S6 kinase2 ), either directly orindirectly (through Immunoglobulin-binding protein 1 ( IGBP1 ) and Proteinphosphatase 2A ( PP2A ). p70 S6 kinase s activation is also regulated byits phosphorylation by protein kinase C zeta type ( PKC-zeta ) and/or PDK.p70 S6 kinase s activate co-factor eIF4B . Another pathway that regulates eIF4 phosphorylation involves Mitogen-activatedprotein family kinases, specifically Mitogen-activated protein kinases Erk andp38. Erk is activated through the sequential activation of Ras (viaguanosine 5'-triphosphate exchange), proto-oncogen serine/threonine-protein kinase,c-Raf-1 (via membrane recruitment and phosphorylation), and then dual specificityMAP kinases ( MEK1 and MEK2 ). p38 pathway is involved in theregulation 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 Gprotein-coupled receptor agonists (e.g., Thrombin) . Extracellular signal may be transferred to MAPK cascade through eitherRas-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 CDC42activate Mitogen-activated protein kinase kinase kinases ( MAP3Ks ) directly (e.g.mitogen-activated protein kinase kinase kinase 11 ( MLK3 )) or via p21 proteinactivated kinase 1 ( PAK1 ) (e.g. Mitogen-activated protein kinase kinase kinase 1( MAP3K1 )) . Some of MAP3K s are activated by distinct extracellular stimuli. For example,Mitogen-activated protein kinase kinase kinase 7 ( TAK1 ) is activated byTransforming growth factor beta ( TGF-beta ) and cytokines ,. Consequently, MAP3K s phosphorylate two serine/threonine residues in theactivation/phosphorylation sites of the defined MAP2K s, Mitogen-activated proteinkinase kinase 3, 4 and ( MEK3, MEK4 and MEK6 ) , whichphosphorylate p38 mitogen-activated protein kinase isoforms ,, . p38, as well as Erk activates duallyregulated 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 withEukaryotic translation initiation factor 4E binding protein 1 ( 4E-BP1 ) . Phosphorylation of eIF4E by MNK1 is regulated by competitiveprotein binding with eIF4G1/3 and eIF4G2 . The eIF4E -binding motif of 4E-BP1 interacts with a region ofeIF4E that also binds to eIF4G. Therefore, interaction of 4E-BP1with eIF4E blocks eIF4F complex formation by preventing binding ofeIF4G to eIF4E. Phosphorylation of 4E-BP1 by MNK1 andMSK antagonizes its binding to eIF4E , .During mitogenic conditions, nutrient surplus, and early adenovirus infection,4E-BP1 becomes phosphorylated and dissociates from eIF4E .