EIF4EBP1

EIF4EBP1（eukaryotic translation initiation factor 4E-binding protein 1）または4E-BP1は、ヒトではEIF4EBP1遺伝子にコードされるタンパク質である。4E-BP1は翻訳開始因子eIF4Eに結合することでキャップ依存的翻訳を阻害する。4E-BP1はリン酸化によってeIF4Eから放出され、その結果キャップ依存的翻訳が継続されてタンパク質合成速度が高まる。 リン酸化された4E-BP1は、上流のシグナル伝達（mTORシグナル）の活性化のマーカーとなると考えられている。4E-BP1には7カ所のリン酸化部位が存在し、中でも重要なのはリン酸化の開始部位であるThr37/Thr46、2番目の部位であるThr70、そして最終部位であるSer65である。しかしながら、Ser65とThr70のリン酸化だけでは4E-BP1による翻訳阻害の遮断には不十分であり、複数のリン酸化イベントが組み合わさることでタンパク質合成速度の上昇が引き起こされていることが示唆されている。 4E-BP1はeIF4Eと直接相互作用する。eIF4Eは、リボソーム40SサブユニットをmRNAの5'末端へリクルートするタンパク質複合体（eIF4F）の限定因子となっている。4E-BP1とeIF4Eの相互作用により、この複合体の組み立てが阻害され、翻訳は抑制される。4E-BP1のリン酸化は紫外線照射やインスリンシグナルなどさまざまなシグナルに応答して生じ、eIF4Eからの解離を引き起こしてキャップ依存的翻訳を活性化する。 4E-BP1の高レベルのリン酸化はヒトのがんで幅広く報告されており、そのいくつかでは予後不良と関係している。 4E-BP1は次に挙げる因子と相互作用することが示されている。 eIF4E RPTOR mTOR ^ a b c GRCh38: Ensembl release 89: ENSG00000187840 - Ensembl, May 2017 ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031490 - Ensembl, May 2017 ^ Human PubMed Reference: ^ Mouse PubMed Reference: ^ “Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function”. Nature 371 (6500): 762–767. (November 1994). Bibcode: 1994Natur.371..762P. doi:10.1038/371762a0. PMID 7935836.  ^ 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. doi:10.1038/371762a0. ISSN 0028-0836. http://dx.doi.org/10.1038/371762a0.  ^ Gingras, Anne-Claude; Raught, Brian; Gygi, Steven P.; Niedzwiecka, Anna; Miron, Mathieu; Burley, Stephen K.; Polakiewicz, Roberto D.; Wyslouch-Cieszynska, Aleksandra et al. (2001-11-01). “Hierarchical phosphorylation of the translation inhibitor 4E-BP1”. Genes & Development 15 (21): 2852–2864. doi:10.1101/gad.912401. ISSN 0890-9369. http://dx.doi.org/10.1101/gad.912401.  ^ “EIF4EBP1 eukaryotic translation initiation factor 4E binding protein 1 [Homo sapiens (human) - Gene - NCBI]”. www.ncbi.nlm.nih.gov. 2023年11月11日閲覧。 ^ Qin, Xiaoyu; Jiang, Bin; Zhang, Yanjie (18 March 2016). “4E-BP1, a multifactor regulated multifunctional protein”. Cell Cycle 15 (6): 781–786. doi:10.1080/15384101.2016.1151581. PMC 4845917. PMID 26901143. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845917/.  ^ “Towards a proteome-scale map of the human protein-protein interaction network”. Nature 437 (7062): 1173–8. (October 2005). Bibcode: 2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514.  ^ “Large-scale mapping of human protein-protein interactions by mass spectrometry”. Mol. Syst. Biol. 3: 89. (2007). doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948/.  ^ “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. (September 1995). doi:10.1128/MCB.15.9.4990. PMC 230746. PMID 7651417. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC230746/.  ^ “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. (October 2005). doi:10.1593/neo.05361. PMC 1502028. PMID 16242075. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1502028/.  ^ a b “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. (July 2006). doi:10.1111/j.1365-2443.2006.00977.x. PMID 16824195.  ^ “Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR”. FEBS Lett. 453 (3): 387–90. (June 1999). doi:10.1016/s0014-5793(99)00762-0. PMID 10405182.  ^ “Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors”. Eur. J. Biochem. 269 (12): 3076–85. (June 2002). doi:10.1046/j.1432-1033.2002.02992.x. PMID 12071973.  ^ “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. (April 2000). doi:10.1074/jbc.275.15.10779. PMID 10753870.  ^ “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. (March 2000). doi:10.1093/emboj/19.5.1087. PMC 305647. PMID 10698949. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC305647/.  ^ “Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism”. Genes Dev. 13 (11): 1422–37. (June 1999). doi:10.1101/gad.13.11.1422. PMC 316780. PMID 10364159. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC316780/.  ^ “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. (May 2006). doi:10.1128/MCB.26.10.3955-3965.2006. PMC 1489005. PMID 16648488. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1489005/.  ^ “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. (October 2001). doi:10.1248/cpb.49.1299. PMID 11605658.  ^ “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. (January 2009). doi:10.1152/ajpendo.90752.2008. PMC 2636991. PMID 18957614. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636991/.  ^ a b “TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function”. Curr. Biol. 13 (10): 797–806. (May 2003). doi:10.1016/s0960-9822(03)00329-4. PMID 12747827.  ^ a b “Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action”. Cell 110 (2): 177–89. (July 2002). doi:10.1016/s0092-8674(02)00833-4. PMID 12150926.  ^ a b “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. (August 2006). doi:10.1074/jbc.M603566200. PMID 16798736.  ^ a b “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. (April 2005). doi:10.1128/MCB.25.7.2558-2572.2005. PMC 1061630. PMID 15767663. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1061630/.  ^ “PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals”. Cell. Signal. 18 (12): 2283–91. (December 2006). doi:10.1016/j.cellsig.2006.05.021. PMID 16837165.  ^ “Target of rapamycin (TOR)-signaling and RAIP motifs play distinct roles in the mammalian TOR-dependent phosphorylation of initiation factor 4E-binding protein 1”. J. Biol. Chem. 278 (42): 40717–22. (October 2003). doi:10.1074/jbc.M308573200. PMID 12912989.  ^ “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. (May 2003). doi:10.1074/jbc.C200665200. PMID 12604610.  ^ “mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery”. Cell 110 (2): 163–75. (July 2002). doi:10.1016/s0092-8674(02)00808-5. PMID 12150925.  ^ “Rheb binds and regulates the mTOR kinase”. Curr. Biol. 15 (8): 702–13. (April 2005). doi:10.1016/j.cub.2005.02.053. PMID 15854902.  ^ “Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro”. Genes Cells 5 (9): 765–75. (September 2000). doi:10.1046/j.1365-2443.2000.00365.x. PMID 10971657.  ^ “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). Bibcode: 1998PNAS...95.1432B. doi:10.1073/pnas.95.4.1432. PMC 19032. PMID 9465032. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC19032/.  “4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications”. Cancer Res. 67 (16): 7551–7555. (2007). doi:10.1158/0008-5472.CAN-07-0881. PMID 17699757.  “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). doi:10.1128/MCB.15.9.4990. PMC 230746. PMID 7651417. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC230746/.  “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). doi:10.1016/S0021-9258(17)31637-X. PMID 8083223.  “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). doi:10.1002/j.1460-2075.1995.tb00257.x. PMC 394685. PMID 8521827. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC394685/.  “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). doi:10.1128/MCB.16.10.5450. PMC 231545. PMID 8816458. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC231545/.  “The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth”. Oncogene 13 (11): 2415–20. (1997). PMID 8957083.  “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). doi:10.1006/geno.1996.0638. PMID 8975712.  “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). doi:10.1074/jbc.272.15.10240. PMID 9092573.  “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). doi:10.1074/jbc.272.51.32547. PMID 9405468.  “RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1”. Proc. Natl. Acad. Sci. U.S.A. 95 (4): 1432–1437. (1998). Bibcode: 1998PNAS...95.1432B. doi:10.1073/pnas.95.4.1432. PMC 19032. PMID 9465032. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC19032/.  “PRAK, a novel protein kinase regulated by the p38 MAP kinase”. EMBO J. 17 (12): 3372–3384. (1998). doi:10.1093/emboj/17.12.3372. PMC 1170675. PMID 9628874. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1170675/.  “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). doi:10.1042/bj3360039. PMC 1219839. PMID 9806882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219839/.  “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). doi:10.1128/MCB.19.3.1871. PMC 83980. PMID 10022874. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC83980/.  “Phosphorylation of human MAD1 by the BUB1 kinase in vitro”. Biochem. Biophys. Res. Commun. 257 (2): 589–595. (1999). doi:10.1006/bbrc.1999.0514. PMID 10198256.  “Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism”. Genes Dev. 13 (11): 1422–1437. (1999). doi:10.1101/gad.13.11.1422. PMC 316780. PMID 10364159. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC316780/.  “Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR”. FEBS Lett. 453 (3): 387–390. (1999). doi:10.1016/S0014-5793(99)00762-0. PMID 10405182.  “Substrate specificities and identification of putative substrates of ATM kinase family members”. J. Biol. Chem. 274 (53): 37538–37543. (2000). doi:10.1074/jbc.274.53.37538. PMID 10608806.  “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). doi:10.1128/MCB.20.10.3558-3567.2000. PMC 85648. PMID 10779345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC85648/.  “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). doi:10.1074/jbc.M006005200. PMID 10942774.