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EIF4EBP1

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EIF4EBP1
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesEIF4EBP1,4E-BP1, 4EBP1, BP-1, PHAS-I, eukaryotic translation initiation factor 4E binding protein 1
External IDsOMIM:602223;MGI:103267;HomoloGene:3021;GeneCards:EIF4EBP1;OMA:EIF4EBP1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1978

13685

Ensembl

ENSG00000187840

ENSMUSG00000031490

UniProt

Q13541

Q60876

RefSeq (mRNA)

NM_004095

NM_007918

RefSeq (protein)

NP_004086

NP_031944

Location (UCSC)Chr 8: 38.03 – 38.06 MbChr 8: 27.75 – 27.77 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Eukaryotic translation initiation factor 4E-binding protein 1(also known as 4E-BP1) is aproteinthat in humans is encoded by theEIF4EBP1gene.[5]inhibits cap-dependent translation by binding to translation initiation factor eIF4E. Phosphorylation of 4E-BP1 results in its release from eIF4E, thereby allows cap-dependent translation to continue thereby increasing the rate of protein synthesis.[6]

Phosphorylation[edit]

Phosphorylated 4E-BP1 is thought to be a marker of upstream signaling (mTOR) activation. 4E-BP1 has seven phospho-sites, the three most important of which are the initiation site Thr 37/Thr 46, the second site Thr 70, and the final site Ser65. Moreover, phosphorylation of Ser 65 and Thr 70 alone was not sufficient to block the inhibition of mRNA translation by 4E-BP1, suggesting that multiple phosphorylation events must be combined to increase the rate of protein synthesis.[7]

Function[edit]

This gene encodes one member of a family of translation repressor proteins. The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is a limiting component of the multisubunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. Interaction of this protein with eIF4E inhibits complex assembly and represses translation. This protein is phosphorylated in response to various signals including UV irradiation and insulin signaling, resulting in its dissociation from eIF4E and activation of cap-dependent mRNA translation.[8]

High level of phosphorylated 4E-BP1 has been widely reported in human cancers, and is associated with a worse outcome in several malignancies.[9]

Interactions[edit]

EIF4EBP1 has been shown tointeractwith:

References[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000187840–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000031490–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Sonenberg N (November 1994). "Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function".Nature.371(6500): 762–767.Bibcode:1994Natur.371..762P.doi:10.1038/371762a0.PMID7935836.S2CID4360955.
  6. ^Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Sonenberg N (1994-10-27)."Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function".Nature.371(6500): 762–767.Bibcode:1994Natur.371..762P.doi:10.1038/371762a0.ISSN0028-0836.PMID7935836.S2CID4360955.
  7. ^Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N (2001-11-01)."Hierarchical phosphorylation of the translation inhibitor 4E-BP1".Genes & Development.15(21): 2852–2864.doi:10.1101/gad.912401.ISSN0890-9369.PMC312813.PMID11691836.
  8. ^EntrezGene1978
  9. ^Qin X, Jiang B, Zhang Y (18 March 2016)."4E-BP1, a multifactor regulated multifunctional protein".Cell Cycle.15(6): 781–786.doi:10.1080/15384101.2016.1151581.PMC4845917.PMID26901143.
  10. ^Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network".Nature.437(7062): 1173–8.Bibcode:2005Natur.437.1173R.doi:10.1038/nature04209.PMID16189514.S2CID4427026.
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  12. ^Mader S, Lee H, Pause A, Sonenberg N (September 1995)."The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins".Mol. Cell. Biol.15(9): 4990–7.doi:10.1128/MCB.15.9.4990.PMC230746.PMID7651417.
  13. ^Rao RD, Mladek AC, Lamont JD, Goble JM, Erlichman C, James CD, Sarkaria JN (October 2005)."Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells".Neoplasia.7(10): 921–9.doi:10.1593/neo.05361.PMC1502028.PMID16242075.
  14. ^abEguchi S, Tokunaga C, Hidayat S, Oshiro N, Yoshino K, Kikkawa U, Yonezawa K (July 2006)."Different roles for the TOS and RAIP motifs of the translational regulator protein 4E-BP1 in the association with raptor and phosphorylation by mTOR in the regulation of cell size".Genes Cells.11(7): 757–66.doi:10.1111/j.1365-2443.2006.00977.x.PMID16824195.S2CID30113895.
  15. ^Yang D, Brunn GJ, Lawrence JC (June 1999)."Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR".FEBS Lett.453(3): 387–90.doi:10.1016/s0014-5793(99)00762-0.PMID10405182.S2CID5023204.
  16. ^Patel J, McLeod LE, Vries RG, Flynn A, Wang X, Proud CG (June 2002)."Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors".Eur. J. Biochem.269(12): 3076–85.doi:10.1046/j.1432-1033.2002.02992.x.PMID12071973.
  17. ^Kumar V, Sabatini D, Pandey P, Gingras AC, Majumder PK, Kumar M, Yuan ZM, Carmichael G, Weichselbaum R, Sonenberg N, Kufe D, Kharbanda S (April 2000)."Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase".J. Biol. Chem.275(15): 10779–87.doi:10.1074/jbc.275.15.10779.PMID10753870.
  18. ^Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S (March 2000)."Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation".EMBO J.19(5): 1087–97.doi:10.1093/emboj/19.5.1087.PMC305647.PMID10698949.
  19. ^Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N (June 1999)."Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism".Genes Dev.13(11): 1422–37.doi:10.1101/gad.13.11.1422.PMC316780.PMID10364159.
  20. ^Connolly E, Braunstein S, Formenti S, Schneider RJ (May 2006)."Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells".Mol. Cell. Biol.26(10): 3955–65.doi:10.1128/MCB.26.10.3955-3965.2006.PMC1489005.PMID16648488.
  21. ^Shen X, Tomoo K, Uchiyama S, Kobayashi Y, Ishida T (October 2001)."Structural and thermodynamic behavior of eukaryotic initiation factor 4E in supramolecular formation with 4E-binding protein 1 and mRNA cap analogue, studied by spectroscopic methods".Chem. Pharm. Bull.49(10): 1299–303.doi:10.1248/cpb.49.1299.PMID11605658.
  22. ^Adegoke OA, Chevalier S, Morais JA, Gougeon R, Kimball SR, Jefferson LS, Wing SS, Marliss EB (January 2009)."Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men".Am. J. Physiol. Endocrinol. Metab.296(1): E105–13.doi:10.1152/ajpendo.90752.2008.PMC2636991.PMID18957614.
  23. ^abSchalm SS, Fingar DC, Sabatini DM, Blenis J (May 2003)."TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function".Curr. Biol.13(10): 797–806.Bibcode:2003CBio...13..797S.doi:10.1016/s0960-9822(03)00329-4.PMID12747827.S2CID10326807.
  24. ^abHara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (July 2002)."Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action".Cell.110(2): 177–89.doi:10.1016/s0092-8674(02)00833-4.PMID12150926.S2CID6438316.
  25. ^abWang L, Rhodes CJ, Lawrence JC (August 2006)."Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex 1".J. Biol. Chem.281(34): 24293–303.doi:10.1074/jbc.M603566200.PMID16798736.
  26. ^abWang X, Beugnet A, Murakami M, Yamanaka S, Proud CG (April 2005)."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.25(7): 2558–72.doi:10.1128/MCB.25.7.2558-2572.2005.PMC1061630.PMID15767663.
  27. ^Ha SH, Kim DH, Kim IS, Kim JH, Lee MN, Lee HJ, Kim JH, Jang SK, Suh PG, Ryu SH (December 2006). "PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals".Cell. Signal.18(12): 2283–91.doi:10.1016/j.cellsig.2006.05.021.PMID16837165.
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  29. ^Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K (May 2003)."The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif".J. Biol. Chem.278(18): 15461–4.doi:10.1074/jbc.C200665200.PMID12604610.
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  33. ^Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (February 1998)."RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1".Proc. Natl. Acad. Sci. U.S.A.95(4): 1432–7.Bibcode:1998PNAS...95.1432B.doi:10.1073/pnas.95.4.1432.PMC19032.PMID9465032.

Further reading[edit]

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