Eif4ebp1

Summary

Gene Symbol: Eif4ebp1
Description: eukaryotic translation initiation factor 4E binding protein 1
Alias: PHAS-I, eukaryotic translation initiation factor 4E-binding protein 1, 4E-BP1, eIF4E-binding protein 1, phosphorylated heat- and acid-stable protein regulated by insulin 1
Species: rat
Products:     Eif4ebp1

Top Publications

  1. Lynch M, Fitzgerald C, Johnston K, Wang S, Schmidt E. Activated eIF4E-binding protein slows G1 progression and blocks transformation by c-myc without inhibiting cell growth. J Biol Chem. 2004;279:3327-39 pubmed
    ..It further identifies G(1) control by translation initiation factors as an essential genetic target of c-myc that is necessary for its ability to transform cells. ..
  2. Lin T, Kong X, Haystead T, Pause A, Belsham G, Sonenberg N, et al. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science. 1994;266:653-6 pubmed
    ..Thus, PHAS-I may be a key mediator of the stimulation of protein synthesis by the diverse group of agents and stimuli that activate MAP kinase. ..
  3. Wang X, Beugnet A, Murakami M, Yamanaka S, Proud C. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol. 2005;25:2558-72 pubmed
    ..These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling. ..
  4. Ma X, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307-18 pubmed publisher
    ..Here, we highlight recent findings on the regulators and effectors of mTOR and discuss specific cases that serve as paradigms for the different modes of mTOR regulation and its control of translation. ..
  5. Gingras A, Gygi S, Raught B, Polakiewicz R, Abraham R, Hoekstra M, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 1999;13:1422-37 pubmed
    ..Taken together, our results suggest that 4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylation of the carboxy-terminal serum-sensitive sites. ..
  6. Heesom K, Denton R. Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase. FEBS Lett. 1999;457:489-93 pubmed
    ..This phosphorylation, which occurs predominantly on S(64), results in the dissociation of 4E-BP1 from eIF-4E. ..
  7. Kimball S, Siegfried B, Jefferson L. Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem. 2004;279:54103-9 pubmed
    ..Amino acids also enhance AMPK phosphorylation, although to a lesser extent than glucagon and amino acids combined. ..
  8. Yang D, Kastan M. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol. 2000;2:893-8 pubmed
    ..Through this mechanism, a lack of ATM activity probably contributes to some of the metabolic abnormalities, such as poor growth and insulin resistance, reported in ataxia telangiectasia cells and patients with ataxia telangiectasia. ..
  9. Gosselin P, Martineau Y, Morales J, Czjzek M, Glippa V, Gauffeny I, et al. Tracking a refined eIF4E-binding motif reveals Angel1 as a new partner of eIF4E. Nucleic Acids Res. 2013;41:7783-92 pubmed publisher
    ..Taken together, our results illustrate that we developed a powerful method for identifying new eIF4E partners and open new perspectives for understanding eIF4E-specific regulation. ..
  10. Yanagiya A, Suyama E, Adachi H, Svitkin Y, Aza Blanc P, Imataka H, et al. Translational homeostasis via the mRNA cap-binding protein, eIF4E. Mol Cell. 2012;46:847-58 pubmed publisher
    ..Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination. ..

Detail Information

Publications53

  1. Lynch M, Fitzgerald C, Johnston K, Wang S, Schmidt E. Activated eIF4E-binding protein slows G1 progression and blocks transformation by c-myc without inhibiting cell growth. J Biol Chem. 2004;279:3327-39 pubmed
    ..It further identifies G(1) control by translation initiation factors as an essential genetic target of c-myc that is necessary for its ability to transform cells. ..
  2. Lin T, Kong X, Haystead T, Pause A, Belsham G, Sonenberg N, et al. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science. 1994;266:653-6 pubmed
    ..Thus, PHAS-I may be a key mediator of the stimulation of protein synthesis by the diverse group of agents and stimuli that activate MAP kinase. ..
  3. Wang X, Beugnet A, Murakami M, Yamanaka S, Proud C. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol. 2005;25:2558-72 pubmed
    ..These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling. ..
  4. Ma X, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307-18 pubmed publisher
    ..Here, we highlight recent findings on the regulators and effectors of mTOR and discuss specific cases that serve as paradigms for the different modes of mTOR regulation and its control of translation. ..
  5. Gingras A, Gygi S, Raught B, Polakiewicz R, Abraham R, Hoekstra M, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 1999;13:1422-37 pubmed
    ..Taken together, our results suggest that 4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylation of the carboxy-terminal serum-sensitive sites. ..
  6. Heesom K, Denton R. Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase. FEBS Lett. 1999;457:489-93 pubmed
    ..This phosphorylation, which occurs predominantly on S(64), results in the dissociation of 4E-BP1 from eIF-4E. ..
  7. Kimball S, Siegfried B, Jefferson L. Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem. 2004;279:54103-9 pubmed
    ..Amino acids also enhance AMPK phosphorylation, although to a lesser extent than glucagon and amino acids combined. ..
  8. Yang D, Kastan M. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol. 2000;2:893-8 pubmed
    ..Through this mechanism, a lack of ATM activity probably contributes to some of the metabolic abnormalities, such as poor growth and insulin resistance, reported in ataxia telangiectasia cells and patients with ataxia telangiectasia. ..
  9. Gosselin P, Martineau Y, Morales J, Czjzek M, Glippa V, Gauffeny I, et al. Tracking a refined eIF4E-binding motif reveals Angel1 as a new partner of eIF4E. Nucleic Acids Res. 2013;41:7783-92 pubmed publisher
    ..Taken together, our results illustrate that we developed a powerful method for identifying new eIF4E partners and open new perspectives for understanding eIF4E-specific regulation. ..
  10. Yanagiya A, Suyama E, Adachi H, Svitkin Y, Aza Blanc P, Imataka H, et al. Translational homeostasis via the mRNA cap-binding protein, eIF4E. Mol Cell. 2012;46:847-58 pubmed publisher
    ..Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination. ..
  11. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:177-89 pubmed
    ..elegans raptor yields an array of phenotypes that closely resemble those produced by inactivation of Ce-TOR. Thus, raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo. ..
  12. Hu C, Pang S, Kong X, Velleca M, Lawrence J. Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. Proc Natl Acad Sci U S A. 1994;91:3730-4 pubmed
    ..However, in view of its tissue distribution and the fact that the protein is phosphorylated in response to insulin, we speculate that PHAS-I is important in insulin action. ..
  13. Ayuso M, Hernández Jiménez M, Martín M, Salinas M, Alcazar A. New hierarchical phosphorylation pathway of the translational repressor eIF4E-binding protein 1 (4E-BP1) in ischemia-reperfusion stress. J Biol Chem. 2010;285:34355-63 pubmed publisher
    ..These data help to elucidate the physiological role of 4E-BP1 phosphorylation in controlling protein synthesis. ..
  14. Brunn G, Hudson C, Sekulic A, Williams J, Hosoi H, Houghton P, et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science. 1997;277:99-101 pubmed
    ..These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells. ..
  15. Xu J, Zhao X, Yaster M, Tao Y. Expression and distribution of mTOR, p70S6K, 4E-BP1, and their phosphorylated counterparts in rat dorsal root ganglion and spinal cord dorsal horn. Brain Res. 2010;1336:46-57 pubmed publisher
    ..Our findings support the view that mTOR and its downstream effectors do not play a key role in acute pain. ..
  16. Tee A, Proud C. Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Mol Cell Biol. 2002;22:1674-83 pubmed
    ..This suggests that the N-terminal sequence of 4E-BP1 is required for optimal regulation of 4E-BPs by insulin. ..
  17. Kenerson H, Aicher L, True L, Yeung R. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 2002;62:5645-50 pubmed
    ..Our data provide in vivo evidence that the mTOR pathway is aberrantly activated in TSC renal pathology and that treatment with rapamycin appears effective in the preclinical setting. ..
  18. Otulakowski G, Duan W, O Brodovich H. Global and gene-specific translational regulation in rat lung development. Am J Respir Cell Mol Biol. 2009;40:555-67 pubmed publisher
    ..Translational regulation of IL-18 and protein phosphatase 1 regulatory (inhibitor) subunit 2 is gene-specific, as these changes contrast with the corresponding global changes in polysome abundance. ..
  19. Ban H, Shigemitsu K, Yamatsuji T, Haisa M, Nakajo T, Takaoka M, et al. Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells. Int J Mol Med. 2004;13:537-43 pubmed
    ..In conclusion, l-Arginine regulates p70 S6 kinase activity and phosphorylation of 4E-BP1 through mTOR signaling pathway, which involves system y(+), cationic amino acid transporters. ..
  20. Sui L, Wang J, Li B. Administration of triiodo-L-thyronine into dorsal hippocampus alters phosphorylation of Akt, mammalian target of rapamycin, p70S6 kinase and 4E-BP1 in rats. Neurochem Res. 2008;33:1065-76 pubmed
  21. Coffman K, Yang B, Lu J, Tetlow A, Pelliccio E, Lu S, et al. Characterization of the Raptor/4E-BP1 interaction by chemical cross-linking coupled with mass spectrometry analysis. J Biol Chem. 2014;289:4723-34 pubmed publisher
    ..Furthermore, mutations of residues in the RCR decrease the ability of 4E-BP1 to serve as a substrate for mTORC1 in vitro and in vivo. ..
  22. Haystead T, Haystead C, Hu C, Lin T, Lawrence J. Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. J Biol Chem. 1994;269:23185-91 pubmed
    ..We conclude that PHAS-I is a substrate for MAP kinase both in vivo and in vitro. As PHAS-I is one of the most prominent insulin-stimulated phosphoproteins in adipocytes, it may qualify as the major MAP kinase substrate in these cells. ..
  23. Lin W, Wadlington N, Chen L, Zhuang X, Brorson J, Kang U. Loss of PINK1 attenuates HIF-1? induction by preventing 4E-BP1-dependent switch in protein translation under hypoxia. J Neurosci. 2014;34:3079-89 pubmed publisher
  24. O Loghlen A, Pérez Morgado M, Salinas M, Martin M. N-acetyl-cysteine abolishes hydrogen peroxide-induced modification of eukaryotic initiation factor 4F activity via distinct signalling pathways. Cell Signal. 2006;18:21-31 pubmed
    ..Altogether our findings suggest that the effects caused by oxidative stress on eIF4s factors depends on two MAP kinase-independent signal transduction pathways, being at least one of them rapamycin-dependent. ..
  25. Takabatake M, Daino K, Imaoka T, Nishimura M, Morioka T, Fukushi M, et al. Aberrant expression and phosphorylation of 4E-BP1, a main target of mTOR signaling, in rat mammary carcinomas: an association with etiology. In Vivo. 2011;25:853-60 pubmed
    ..Expression of 4E-BP1 isoforms varied among rat mammary carcinomas, their phosphorylation level being low in MNU-induced carcinomas, suggesting an association of mTOR activity with cancer etiology. ..
  26. Zhou Q, Liu C, Liu W, Zhang H, Zhang R, Liu J, et al. Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, leading to neuronal apoptosis. Toxicol Sci. 2015;143:81-96 pubmed publisher
    ..Our findings suggest that rotenone-induced neuronal loss in PD may be prevented by activating mTOR signaling and/or administering antioxidants. ..
  27. Anthony T, Reiter A, Anthony J, Kimball S, Jefferson L. Deficiency of dietary EAA preferentially inhibits mRNA translation of ribosomal proteins in liver of meal-fed rats. Am J Physiol Endocrinol Metab. 2001;281:E430-9 pubmed
    ..Additionally, the translation of rp mRNAs is preferentially repressed in association with decreased S6K1 phosphorylation...
  28. Stephenson A, Christian J, Seidel E. Polyamines regulate eukaryotic initiation factor 4E-binding protein 1 gene transcription. Biochem Biophys Res Commun. 2004;323:204-12 pubmed
    ..These data provide a mechanism by which polyamines affect transcription of the 4E-BP1 gene, which in turn affect translation of ODC and perhaps other cap-dependent proteins. ..
  29. Fadden P, Haystead T, Lawrence J. Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes. J Biol Chem. 1997;272:10240-7 pubmed
    ..All five sites identified fit a (Ser/Thr)-Pro motif, suggesting that the phosphorylation of PHAS-I in cells is mediated by a proline-directed protein kinase. ..
  30. Mezey E, Rennie Tankersley L, Potter J. Effect of leptin on liver alcohol dehydrogenase. Biochem Biophys Res Commun. 2005;337:1324-9 pubmed
    ..The effect of leptin in enhancing translational initiating factors may be of significance in the regulation not only of ADH but also of many other proteins. ..
  31. Thomson D, Fick C, Gordon S. AMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions. J Appl Physiol (1985). 2008;104:625-32 pubmed publisher
  32. Tinton S, Buc Calderon P. Hypoxia increases the association of 4E-binding protein 1 with the initiation factor 4E in isolated rat hepatocytes. FEBS Lett. 1999;446:55-9 pubmed
    ..Although hypoxia might be signalling via the rapamycin-sensitive pathway by changing eIF-4E availability, such a pathway is unlikely to be responsible for the depression in overall protein synthesis under hypoxia. ..
  33. Petegnief V, Font Nieves M, Martín M, Salinas M, Planas A. Nitric oxide mediates NMDA-induced persistent inhibition of protein synthesis through dephosphorylation of eukaryotic initiation factor 4E-binding protein 1 and eukaryotic initiation factor 4G proteolysis. Biochem J. 2008;411:667-77 pubmed publisher
    ..In conclusion, our data show that NO mediates NMDA-induced persistent translation inhibition and suggest that deficient eIF4F activity contributes to this process. ..
  34. Sun G, Kobayashi T, Abe M, Tada N, Adachi H, Shiota A, et al. The endoplasmic reticulum stress-inducible protein Niban regulates eIF2alpha and S6K1/4E-BP1 phosphorylation. Biochem Biophys Res Commun. 2007;360:181-7 pubmed
    ..Additionally, suppression of NIBAN expression in HeLa cells promoted apoptosis. Together these results suggest that Niban is involved in the ER stress response, and that Niban can modulate cell death signaling by regulating translation. ..
  35. Lin T, Kong X, Saltiel A, Blackshear P, Lawrence J. Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J Biol Chem. 1995;270:18531-8 pubmed
    ..Rapamycin may inhibit translation initiation by increasing PHAS-I binding to eIF-4E. ..
  36. Funai K, Parkington J, Carambula S, Fielding R. Age-associated decrease in contraction-induced activation of downstream targets of Akt/mTor signaling in skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1080-6 pubmed
    ..These observations suggest that the anabolic response to muscle stimulation is attenuated with aging and may contribute to the limited capacity of hypertrophy in aged animals. ..
  37. Vary T, Lang C. IGF-I activates the eIF4F system in cardiac muscle in vivo. Mol Cell Biochem. 2005;272:209-20 pubmed
    ..Furthermore, the results are consistent with a role for assembly of active eIF4G.eIF4E complex and activation of S6K1 in mediating the stimulation of mRNA translation initiation by IGF-I through a PKB/mTOR signaling pathway. ..
  38. Duan P, Hu C, Quan C, Yu T, Huang W, Chen W, et al. 4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells. Toxicol Lett. 2017;267:21-31 pubmed publisher
  39. Otulakowski G, Duan W, Gandhi S, O Brodovich H. Steroid and oxygen effects on eIF4F complex, mTOR, and ENaC translation in fetal lung epithelia. Am J Respir Cell Mol Biol. 2007;37:457-66 pubmed
    ..We speculate that at birth increased Po(2) acts with GC through an mTOR-related pathway to increase alpha-ENaC protein synthesis, thereby promoting lung fluid absorption. ..
  40. Lang C, Frost R. Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. J Cell Physiol. 2005;203:144-55 pubmed
    ..Hence, LPS working via a glucocorticoid-independent mechanism produces a leucine resistance in skeletal muscle that might be expected to impair the ability of this amino acid to stimulate translation initiation and protein synthesis. ..
  41. Potter M, Shah S, Elbirt K, Callery M. Endotoxin (LPS) stimulates 4E-BP1/PHAS-I phosphorylation in macrophages. J Surg Res. 2001;97:54-9 pubmed
    ..LPS stimulates 4E-BP1 phosphorylation in macrophages through FRAP/mTOR signaling. This pathway may contribute to the translational control of cytokine gene expression in macrophages. ..
  42. Ruoff R, Katsara O, Kolupaeva V. Cell type-specific control of protein synthesis and proliferation by FGF-dependent signaling to the translation repressor 4E-BP. Proc Natl Acad Sci U S A. 2016;113:7545-50 pubmed publisher
    ..Thus, our findings demonstrate that FGF signaling differentially impacts protein synthesis through either stimulation or repression, in a cell-type-dependent manner, with 4E-BP1 being a key player. ..
  43. Kim J, Chen J. Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Proc Natl Acad Sci U S A. 2000;97:14340-5 pubmed
    ..These findings uncover a function for the nucleus in the direct regulation of the protein synthesis machinery via extracellular signals. ..
  44. Ohsumi M, Yoshizawa F, Hayase K, Yokogoshi H. Effect of quality and quantity of dietary protein on 4E-BP1 and S6K1 phosphorylation of brains in aged rats. J Nutr Sci Vitaminol (Tokyo). 2010;56:319-25 pubmed
    ..The results suggest that the ingestion of a higher quality and quantity of dietary protein stimulates the phosphorylation of 4E-BP1 and S6K1 in the brain and increases the brain protein synthesis in the aged rats. ..
  45. Dasilva L, Pillon S, Genereaux J, Davey M, Gloor G, Karagiannis J, et al. The C-terminal residues of Saccharomyces cerevisiae Mec1 are required for its localization, stability, and function. G3 (Bethesda). 2013;3:1661-74 pubmed publisher
    ..Our study supports a role for the C-terminus in Mec1 folding and stability, and suggests a role for the proteasome in regulating Mec1 levels. ..
  46. Fingar D, Richardson C, Tee A, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004;24:200-16 pubmed
    ..These data demonstrate that, as for the regulation of cell growth and cell size, the S6K1 and 4E-BP1/eIF4E pathways each represent critical mediators of mTOR-dependent cell cycle control. ..
  47. Su Y, Yu C, Hsu F, Fu S, Hwang J, Hung L, et al. Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway. Int J Mol Med. 2014;34:1417-22 pubmed publisher
    ..Everolimus-mediated radiosensitization is associated with the autophagy pathway. Thus, everolimus is a novel radiosensitizing agent with potential for use in cancer radiotherapy. ..
  48. Bishop J, Nien W, Dauphinee S, Too C. Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells. J Endocrinol. 2006;190:307-12 pubmed
    ..In summary, PRL-stimulated phosphorylation of mTOR is mediated by PI3K. PRL-activated mTOR may phosphorylate p70S6K and 4E-BP1 by restraining PP2A. ..
  49. Marshall S. Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci STKE. 2006;2006:re7 pubmed
  50. Connolly E, Thuillier V, Rouy D, Bouetard G, Schneider R. Inhibition of Cap-initiation complexes linked to a novel mechanism of eIF4G depletion in acute myocardial ischemia. Cell Death Differ. 2006;13:1586-94 pubmed
    ..Acute heart ischemia therefore downregulates cap-dependent translation through eIF4E sequestration triggered by eIF4G depletion. ..
  51. Vary T, Deiter G, Goodman S. Acute alcohol intoxication enhances myocardial eIF4G phosphorylation despite reducing mTOR signaling. Am J Physiol Heart Circ Physiol. 2005;288:H121-8 pubmed
    ..eIF4E complex formation, which appear to be independent of changes in phosphorylation of eIF4G but dependent on mTOR. ..
  52. Xu H, Shen L, Chen X, Ding Y, He J, Zhu J, et al. mTOR/P70S6K promotes spermatogonia proliferation and spermatogenesis in Sprague Dawley rats. Reprod Biomed Online. 2016;32:207-17 pubmed publisher
    ..Therefore, we suggest that mTOR plays an important role in spermatogenesis by regulating p70s6k activation and that 4e-bp1 is either directly or indirectly regulated by PI3K. ..