EIF4EBP1
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:
- EIF4E,[10][11][12][13][14][15][16][17][18][19][20][21][22]
- KIAA1303,[14][23][24][25][26][27][28][29]and
- Mammalian target of rapamycin(mTOR).[23][24][25][26][30][31][32][33]
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000187840–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000031490–Ensembl,May 2017
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- ^EntrezGene1978
- ^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.
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- ^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.
- ^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.
- ^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.
- ^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.
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- ^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.
- ^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.
- ^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.
- ^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.
- ^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.
- ^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.
- ^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.
- ^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.
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- ^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]- Armengol G, Rojo F, Castellví J, Iglesias C, Cuatrecasas M, Pons B, Baselga J, Ramón y Cajal S (2007)."4E-binding protein 1: a key molecular" funnel factor "in human cancer with clinical implications".Cancer Res.67(16): 7551–7555.doi:10.1158/0008-5472.CAN-07-0881.PMID17699757.
- Mader S, Lee H, Pause A, Sonenberg N (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.
- Haystead TA, Haystead CM, Hu C, Lin TA, Lawrence JC (1994)."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.269(37): 23185–91.doi:10.1016/S0021-9258(17)31637-X.PMID8083223.
- Haghighat A, Mader S, Pause A, Sonenberg N (1996)."Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E".EMBO J.14(22): 5701–9.doi:10.1002/j.1460-2075.1995.tb00257.x.PMC394685.PMID8521827.
- Feigenblum D, Schneider RJ (1996)."Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation".Mol. Cell. Biol.16(10): 5450–7.doi:10.1128/MCB.16.10.5450.PMC231545.PMID8816458.
- Rousseau D, Gingras AC, Pause A, Sonenberg N (1997). "The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth".Oncogene.13(11): 2415–20.PMID8957083.
- Tsukiyama-Kohara K, Vidal SM, Gingras AC, Glover TW, Hanash SM, Heng H, Sonenberg N (1997). "Tissue distribution, genomic structure, and chromosome mapping of mouse and human eukaryotic initiation factor 4E-binding proteins 1 and 2".Genomics.38(3): 353–363.doi:10.1006/geno.1996.0638.PMID8975712.
- Fadden P, Haystead TA, Lawrence JC (1997)."Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes".J. Biol. Chem.272(15): 10240–10247.doi:10.1074/jbc.272.15.10240.PMID9092573.
- Brunn GJ, Fadden P, Haystead TA, Lawrence JC (1998)."The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus".J. Biol. Chem.272(51): 32547–32550.doi:10.1074/jbc.272.51.32547.PMID9405468.
- Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998)."RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1".Proc. Natl. Acad. Sci. U.S.A.95(4): 1432–1437.Bibcode:1998PNAS...95.1432B.doi:10.1073/pnas.95.4.1432.PMC19032.PMID9465032.
- New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J (1998)."PRAK, a novel protein kinase regulated by the p38 MAP kinase".EMBO J.17(12): 3372–3384.doi:10.1093/emboj/17.12.3372.PMC1170675.PMID9628874.
- Heesom KJ, Avison MB, Diggle TA, Denton RM (1999)."Insulin-stimulated kinase from rat fat cells that phosphorylates initiation factor 4E-binding protein 1 on the rapamycin-insensitive site (serine-111)".Biochem. J.336(1): 39–48.doi:10.1042/bj3360039.PMC1219839.PMID9806882.
- Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR, Cooper JA (1999)."Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo".Mol. Cell. Biol.19(3): 1871–80.doi:10.1128/MCB.19.3.1871.PMC83980.PMID10022874.
- Seeley TW, Wang L, Zhen JY (1999). "Phosphorylation of human MAD1 by the BUB1 kinase in vitro".Biochem. Biophys. Res. Commun.257(2): 589–595.doi:10.1006/bbrc.1999.0514.PMID10198256.
- Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N (1999)."Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism".Genes Dev.13(11): 1422–1437.doi:10.1101/gad.13.11.1422.PMC316780.PMID10364159.
- Yang D, Brunn GJ, Lawrence JC (1999)."Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR".FEBS Lett.453(3): 387–390.doi:10.1016/S0014-5793(99)00762-0.PMID10405182.S2CID5023204.
- Kim ST, Lim DS, Canman CE, Kastan MB (2000)."Substrate specificities and identification of putative substrates of ATM kinase family members".J. Biol. Chem.274(53): 37538–37543.doi:10.1074/jbc.274.53.37538.PMID10608806.
- Mothe-Satney I, Yang D, Fadden P, Haystead TA, Lawrence JC (2000)."Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression".Mol. Cell. Biol.20(10): 3558–3567.doi:10.1128/MCB.20.10.3558-3567.2000.PMC85648.PMID10779345.
- Mothe-Satney I, Brunn GJ, McMahon LP, Capaldo CT, Abraham RT, Lawrence JC (2000)."Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies".J. Biol. Chem.275(43): 33836–33843.doi:10.1074/jbc.M006005200.PMID10942774.