EIF4EBP1
(Redirected from 4EBP1)
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the EIF4EBP1 gene.[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 to interact with:
- 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
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031490 – Ensembl, May 2017
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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. PMC 230746. PMID 7651417.
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- ^ a b Eguchi 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. PMID 16824195. S2CID 30113895.
- ^ 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. PMID 10405182. S2CID 5023204.
- ^ 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. PMID 12071973.
- ^ 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. PMID 10753870.
- ^ 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. PMC 305647. PMID 10698949.
- ^ 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. PMC 316780. PMID 10364159.
- ^ 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. PMC 1489005. PMID 16648488.
- ^ 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. PMID 11605658.
- ^ 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. PMC 2636991. PMID 18957614.
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- ^ a b Wang 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. PMID 16798736.
- ^ a b Wang 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. PMC 1061630. PMID 15767663.
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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. PMC 19032. PMID 9465032.
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. PMID 17699757.
- 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. PMC 230746. PMID 7651417.
- 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. PMID 8083223.
- 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. PMC 394685. PMID 8521827.
- 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. PMC 231545. PMID 8816458.
- 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. PMID 8957083.
- 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. PMID 8975712.
- 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. PMID 9092573.
- 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. PMID 9405468.
- 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. PMC 19032. PMID 9465032.
- 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. PMC 1170675. PMID 9628874.
- 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. PMC 1219839. PMID 9806882.
- 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. PMC 83980. PMID 10022874.
- 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. PMID 10198256.
- 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. PMC 316780. PMID 10364159.
- 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. PMID 10405182. S2CID 5023204.
- 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. PMID 10608806.
- 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. PMC 85648. PMID 10779345.
- 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. PMID 10942774.