PDK (PDPK1), 188.8.131.52, PI3K cat class IA, PKC-zeta, Hamartin, eIF4G1/3, Erk (MAPK1/3), mTOR, p38 MAPK, Tuberin, PI3K reg class IA, PAK1, MNK1, GRB2, IRS-1, TAK1(MAP3K7), IGBP1, eIF4G1, RHEB2, mRNA, c-Raf-1, eIF4E, H-Ras, eIF4H, AKT(PKB), MSK1, MEK1(MAP2K1), EGF, eIF4B, Shc, TGF-beta receptor type II, PtdIns(4,5)P2, TGF-beta 1, eIF4G2, TAB1, SOS, TGF-beta receptor type I, MEK3(MAP2K3), CDC42, Tiam 1, MEK4(MAP2K4), MEKK1(MAP3K1), MEK2(MAP2K2), p70 S6 kinase1, MLK3(MAP3K11), Rac1, MEK6(MAP2K6), PP2A catalytic, 4E-BP1, p70 S6 kinase2, EGFR, eIF4A, PtdIns(3,4,5)P3
Regulation of eIF4
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, eIF4E, eIF4A ). 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 eIF4F .
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 eIF4F phosphorylation.
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 ( 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-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 kinase s activation is also regulated by its 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-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 MAP3K s 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, MAP3K s phosphorylate two serine/threonine residues in the activation/phosphorylation sites of the defined MAP2K s, 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 ( 4E-BP1 ) . 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 eIF4E .