EIF4EBP1 explained

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.^[1] 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.^[2]

Phosphorylation

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.^[3]

Function

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.

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

Interactions

EIF4EBP1 has been shown to interact with:

• EIF4E,^{[5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]}
• KIAA1303,^{[9] [18] [19] [20]} and
• Mammalian target of rapamycin (mTOR).^{[21] [22] [23] [24] [25] [26] [27] [28]}

Further reading

• Armengol G, Rojo F, Castellví J, Iglesias C, Cuatrecasas M, Pons B, Baselga J, Ramón y Cajal S . 4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications . Cancer Res. . 67 . 16 . 7551–7555 . 2007 . 17699757 . 10.1158/0008-5472.CAN-07-0881 . free .
• Mader S, Lee H, Pause A, Sonenberg N . 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 . 1995 . 7651417 . 230746 . 10.1128/MCB.15.9.4990.
• Haystead TA, Haystead CM, Hu C, Lin TA, Lawrence JC . 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 . 1994 . 10.1016/S0021-9258(17)31637-X . 8083223 . free .
• Haghighat A, Mader S, Pause A, Sonenberg N . 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 . 1996 . 8521827 . 394685 . 10.1002/j.1460-2075.1995.tb00257.x.
• Feigenblum D, Schneider RJ . 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 . 1996 . 8816458 . 231545 . 10.1128/MCB.16.10.5450.
• Rousseau D, Gingras AC, Pause A, Sonenberg N . The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth . Oncogene . 13 . 11 . 2415–20 . 1997 . 8957083 .
• Tsukiyama-Kohara K, Vidal SM, Gingras AC, Glover TW, Hanash SM, Heng H, Sonenberg N . 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 . 1997 . 8975712 . 10.1006/geno.1996.0638 .
• Fadden P, Haystead TA, Lawrence JC . 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 . 1997 . 9092573 . 10.1074/jbc.272.15.10240 . free .
• Brunn GJ, Fadden P, Haystead TA, Lawrence JC . 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 . 1998 . 9405468 . 10.1074/jbc.272.51.32547 . free .
• Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM . RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 . Proc. Natl. Acad. Sci. U.S.A. . 95 . 4 . 1432–1437 . 1998 . 9465032 . 19032 . 10.1073/pnas.95.4.1432 . 1998PNAS...95.1432B . free .
• New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J . PRAK, a novel protein kinase regulated by the p38 MAP kinase . EMBO J. . 17 . 12 . 3372–3384 . 1998 . 9628874 . 1170675 . 10.1093/emboj/17.12.3372 .
• Heesom KJ, Avison MB, Diggle TA, Denton RM . 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 . 1999 . 9806882 . 1219839 . 10.1042/bj3360039.
• Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR, Cooper JA . Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo . Mol. Cell. Biol. . 19 . 3 . 1871–80 . 1999 . 10022874 . 83980 . 10.1128/MCB.19.3.1871.
• Seeley TW, Wang L, Zhen JY . Phosphorylation of human MAD1 by the BUB1 kinase in vitro . Biochem. Biophys. Res. Commun. . 257 . 2 . 589–595 . 1999 . 10198256 . 10.1006/bbrc.1999.0514 .
• Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N . Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism . Genes Dev. . 13 . 11 . 1422–1437 . 1999 . 10364159 . 316780 . 10.1101/gad.13.11.1422 .
• Yang D, Brunn GJ, Lawrence JC . Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR . FEBS Lett. . 453 . 3 . 387–390 . 1999 . 10405182 . 10.1016/S0014-5793(99)00762-0 . 5023204 . free .
• Kim ST, Lim DS, Canman CE, Kastan MB . Substrate specificities and identification of putative substrates of ATM kinase family members . J. Biol. Chem. . 274 . 53 . 37538–37543 . 2000 . 10608806 . 10.1074/jbc.274.53.37538 . free .
• Mothe-Satney I, Yang D, Fadden P, Haystead TA, Lawrence JC . Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression . Mol. Cell. Biol. . 20 . 10 . 3558–3567 . 2000 . 10779345 . 85648 . 10.1128/MCB.20.10.3558-3567.2000 .
• Mothe-Satney I, Brunn GJ, McMahon LP, Capaldo CT, Abraham RT, Lawrence JC . 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 . 2000 . 10942774 . 10.1074/jbc.M006005200 . free .

Notes and References

1. Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Sonenberg N . Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function . Nature . 371 . 6500 . 762–767 . November 1994 . 7935836 . 10.1038/371762a0 . 1994Natur.371..762P . 4360955 .
2. Pause . Arnim . Belsham . Graham J. . Gingras . Anne-Claude . Donzé . Olivier . Lin . Tai-An . Lawrence . John C. . Sonenberg . Nahum . 1994-10-27 . Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function . Nature . 371 . 6500 . 762–767 . 10.1038/371762a0 . 7935836 . 1994Natur.371..762P . 4360955 . 0028-0836.
3. Gingras . Anne-Claude . Raught . Brian . Gygi . Steven P. . Niedzwiecka . Anna . Miron . Mathieu . Burley . Stephen K. . Polakiewicz . Roberto D. . Wyslouch-Cieszynska . Aleksandra . Aebersold . Ruedi . Sonenberg . Nahum . 2001-11-01 . Hierarchical phosphorylation of the translation inhibitor 4E-BP1 . Genes & Development . 15 . 21 . 2852–2864 . 10.1101/gad.912401 . 11691836 . 312813 . 0890-9369. free .
4. Qin . Xiaoyu . Jiang . Bin . Zhang . Yanjie . 4E-BP1, a multifactor regulated multifunctional protein . Cell Cycle . 18 March 2016 . 15 . 6 . 781–786 . 10.1080/15384101.2016.1151581 . 26901143 . 4845917 .
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28. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM . RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 . Proc. Natl. Acad. Sci. U.S.A. . 95 . 4 . 1432–7 . February 1998 . 9465032 . 19032 . 10.1073/pnas.95.4.1432. 1998PNAS...95.1432B . free .