4EBP1_HUMAN
ID 4EBP1_HUMAN Reviewed; 118 AA.
AC Q13541; B2R502; D3DSW8; Q6IBN3;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Eukaryotic translation initiation factor 4E-binding protein 1;
DE Short=4E-BP1;
DE Short=eIF4E-binding protein 1;
DE AltName: Full=Phosphorylated heat- and acid-stable protein regulated by insulin 1;
DE Short=PHAS-I;
GN Name=EIF4EBP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606 {ECO:0000312|EMBL:BAB18650.1};
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH EIF4E, AND
RP PHOSPHORYLATION.
RC TISSUE=Placenta;
RX PubMed=7935836; DOI=10.1038/371762a0;
RA Pause A., Belsham G.J., Gingras A.-C., Donze O., Lin T.-A.,
RA Lawrence J.C. Jr., Sonenberg N.;
RT "Insulin-dependent stimulation of protein synthesis by phosphorylation of a
RT regulator of 5'-cap function.";
RL Nature 371:762-767(1994).
RN [2] {ECO:0000312|EMBL:BAB18650.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Ito M., Shichijo S., Tsuda N., Ochi M., Harashima N., Saito N., Itoh K.;
RT "Identification of multiple genes and immunogenic epitopes of pancreatic
RT cancer cells.";
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [3] {ECO:0000312|EMBL:BAB18650.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000312|EMBL:BAB18650.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6] {ECO:0000312|EMBL:BAB18650.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Lung {ECO:0000269|PubMed:15489334};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 2-13, AND ACETYLATION AT SER-2.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass spectrometric
RT identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP INTERACTION WITH EIF4E AND EIF4G.
RX PubMed=8521827; DOI=10.1002/j.1460-2075.1995.tb00257.x;
RA Haghighat A., Mader S., Pause A., Sonenberg N.;
RT "Repression of cap-dependent translation by 4E-binding protein 1:
RT competition with p220 for binding to eukaryotic initiation factor-4E.";
RL EMBO J. 14:5701-5709(1995).
RN [10]
RP PHOSPHORYLATION BY MTOR.
RX PubMed=9465032; DOI=10.1073/pnas.95.4.1432;
RA Burnett P.E., Barrow R.K., Cohen N.A., Snyder S.H., Sabatini D.M.;
RT "RAFT1 phosphorylation of the translational regulators p70 S6 kinase and
RT 4E-BP1.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:1432-1437(1998).
RN [11]
RP INTERACTION WITH RPTOR.
RX PubMed=12150926; DOI=10.1016/s0092-8674(02)00833-4;
RA Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S.,
RA Tokunaga C., Avruch J., Yonezawa K.;
RT "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR
RT action.";
RL Cell 110:177-189(2002).
RN [12]
RP INTERACTION WITH RPTOR, AND PHOSPHORYLATION AT THR-37; THR-46; SER-65 AND
RP THR-70 BY MTOR.
RX PubMed=12747827; DOI=10.1016/s0960-9822(03)00329-4;
RA Schalm S.S., Fingar D.C., Sabatini D.M., Blenis J.;
RT "TOS motif-mediated raptor binding regulates 4E-BP1 multisite
RT phosphorylation and function.";
RL Curr. Biol. 13:797-806(2003).
RN [13]
RP PHOSPHORYLATION AT SER-65; SER-101 AND SER-112, PROTEIN SEQUENCE, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=12588975; DOI=10.1128/mcb.23.5.1546-1557.2003;
RA Wang X., Li W., Parra J.L., Beugnet A., Proud C.G.;
RT "The C terminus of initiation factor 4E-binding protein 1 contains multiple
RT regulatory features that influence its function and phosphorylation.";
RL Mol. Cell. Biol. 23:1546-1557(2003).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-65, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Prostate cancer;
RX PubMed=17487921; DOI=10.1002/elps.200600782;
RA Giorgianni F., Zhao Y., Desiderio D.M., Beranova-Giorgianni S.;
RT "Toward a global characterization of the phosphoproteome in prostate cancer
RT cells: identification of phosphoproteins in the LNCaP cell line.";
RL Electrophoresis 28:2027-2034(2007).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-112, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-50; THR-70 AND SER-101, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37; THR-41; THR-46; THR-50;
RP TYR-54; SER-65; THR-70 AND SER-83, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37 AND THR-46, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37 AND THR-70, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-70 AND SER-112, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [24]
RP FUNCTION, INTERACTION WITH EIF4E, UBIQUITINATION AT LYS-57, PHOSPHORYLATION
RP AT THR-37; THR-46; SER-65 AND THR-70, AND MUTAGENESIS OF THR-37; THR-46;
RP LYS-57; 59-LEU-MET-60; SER-65; LYS-69; THR-70 AND LYS-105.
RX PubMed=22578813; DOI=10.1016/j.molcel.2012.04.004;
RA Yanagiya A., Suyama E., Adachi H., Svitkin Y.V., Aza-Blanc P., Imataka H.,
RA Mikami S., Martineau Y., Ronai Z.A., Sonenberg N.;
RT "Translational homeostasis via the mRNA cap-binding protein, eIF4E.";
RL Mol. Cell 46:847-858(2012).
RN [25]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37; THR-41; SER-65; THR-70;
RP SER-101 AND SER-112, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-65; THR-70 AND THR-77, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [28]
RP PHOSPHORYLATION AT THR-37; THR-46; SER-65 AND THR-70.
RX PubMed=29750193; DOI=10.1126/sciadv.aao5838;
RA Nguyen J.T., Ray C., Fox A.L., Mendonca D.B., Kim J.K., Krebsbach P.H.;
RT "Mammalian EAK-7 activates alternative mTOR signaling to regulate cell
RT proliferation and migration.";
RL Sci. Adv. 4:EAAO5838-EAAO5838(2018).
RN [29]
RP STRUCTURE BY NMR OF 4-118.
RX PubMed=9684899; DOI=10.1002/pro.5560070720;
RA Fletcher C.M., Wagner G.;
RT "The interaction of eIF4E with 4E-BP1 is an induced fit to a completely
RT disordered protein.";
RL Protein Sci. 7:1639-1642(1998).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 36-70 IN COMPLEX WITH EIF4E AND
RP MRNA CAP ANALOG.
RX PubMed=16271312; DOI=10.1016/j.bbapap.2005.07.023;
RA Tomoo K., Matsushita Y., Fujisaki H., Abiko F., Shen X., Taniguchi T.,
RA Miyagawa H., Kitamura K., Miura K., Ishida T.;
RT "Structural basis for mRNA cap-binding regulation of eukaryotic initiation
RT factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal
RT structural, and molecular dynamics simulation methods.";
RL Biochim. Biophys. Acta 1753:191-208(2005).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 51-67 IN COMPLEX WITH EIF4E2 AND
RP MRNA CAP ANALOG.
RX PubMed=17368478; DOI=10.1016/j.jmb.2007.02.019;
RA Rosettani P., Knapp S., Vismara M.-G., Rusconi L., Cameron A.D.;
RT "Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-
RT bound and unliganded forms.";
RL J. Mol. Biol. 368:691-705(2007).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 51-64 IN COMPLEX WITH EIF4E AND
RP MRNA CAP ANALOG.
RX PubMed=17631896; DOI=10.1016/j.jmb.2007.06.033;
RA Brown C.J., McNae I., Fischer P.M., Walkinshaw M.D.;
RT "Crystallographic and mass spectrometric characterisation of eIF4E with N7-
RT alkylated cap derivatives.";
RL J. Mol. Biol. 372:7-15(2007).
RN [33] {ECO:0007744|PDB:4UED}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 50-83 IN COMPLEX WITH EIF4E,
RP INTERACTION WITH EIF4E, AND PHOSPHORYLATION AT SER-65 AND THR-70.
RX PubMed=25702871; DOI=10.1016/j.molcel.2015.01.017;
RA Peter D., Igreja C., Weber R., Wohlbold L., Weiler C., Ebertsch L.,
RA Weichenrieder O., Izaurralde E.;
RT "Molecular architecture of 4E-BP translational inhibitors bound to eIF4E.";
RL Mol. Cell 57:1074-1087(2015).
CC -!- FUNCTION: Repressor of translation initiation that regulates EIF4E
CC activity by preventing its assembly into the eIF4F complex:
CC hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds
CC to EIF4E, leading to repress translation. In contrast,
CC hyperphosphorylated form dissociates from EIF4E, allowing interaction
CC between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation.
CC Mediates the regulation of protein translation by hormones, growth
CC factors and other stimuli that signal through the MAP kinase and mTORC1
CC pathways. {ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:7935836}.
CC -!- SUBUNIT: Hypophosphorylated EIF4EBP1 competes with EIF4G1/EIF4G3 to
CC interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) or
CC mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex
CC allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation
CC (PubMed:12150926, PubMed:16271312, PubMed:17368478, PubMed:17631896,
CC PubMed:22578813, PubMed:7935836, PubMed:8521827, PubMed:25702871).
CC Interacts (via TOS motif) with RPTOR; promoting phosphorylation by
CC mTORC1 (PubMed:12747827). {ECO:0000269|PubMed:12150926,
CC ECO:0000269|PubMed:12747827, ECO:0000269|PubMed:16271312,
CC ECO:0000269|PubMed:17368478, ECO:0000269|PubMed:17631896,
CC ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:25702871,
CC ECO:0000269|PubMed:7935836, ECO:0000269|PubMed:8521827}.
CC -!- INTERACTION:
CC Q13541; Q9UKV8: AGO2; NbExp=2; IntAct=EBI-74090, EBI-528269;
CC Q13541; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-74090, EBI-742054;
CC Q13541; P06730: EIF4E; NbExp=29; IntAct=EBI-74090, EBI-73440;
CC Q13541; A6NMX2: EIF4E1B; NbExp=3; IntAct=EBI-74090, EBI-18394358;
CC Q13541; P25791-3: LMO2; NbExp=3; IntAct=EBI-74090, EBI-11959475;
CC Q13541; P50221: MEOX1; NbExp=3; IntAct=EBI-74090, EBI-2864512;
CC Q13541; P42345: MTOR; NbExp=2; IntAct=EBI-74090, EBI-359260;
CC Q13541; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-74090, EBI-79165;
CC Q13541; P78424: POU6F2; NbExp=3; IntAct=EBI-74090, EBI-12029004;
CC Q13541; Q04864: REL; NbExp=3; IntAct=EBI-74090, EBI-307352;
CC Q13541; Q04864-2: REL; NbExp=3; IntAct=EBI-74090, EBI-10829018;
CC Q13541; Q8N122: RPTOR; NbExp=5; IntAct=EBI-74090, EBI-1567928;
CC Q13541; P15884: TCF4; NbExp=3; IntAct=EBI-74090, EBI-533224;
CC Q13541; Q8N720: ZNF655; NbExp=3; IntAct=EBI-74090, EBI-625509;
CC Q13541; Q9JLN9: Mtor; Xeno; NbExp=2; IntAct=EBI-74090, EBI-1571628;
CC -!- DOMAIN: The TOS motif mediates interaction with RPTOR, leading to
CC promote phosphorylation by mTORC1 complex.
CC {ECO:0000269|PubMed:12747827}.
CC -!- PTM: Phosphorylated on serine and threonine residues in response to
CC insulin, EGF and PDGF. Phosphorylation at Thr-37, Thr-46, Ser-65 and
CC Thr-70, corresponding to the hyperphosphorylated form, is regulated by
CC mTORC1 and abolishes binding to EIF4E. {ECO:0000269|PubMed:12588975,
CC ECO:0000269|PubMed:12747827, ECO:0000269|PubMed:22578813,
CC ECO:0000269|PubMed:7935836, ECO:0000269|PubMed:9465032}.
CC -!- PTM: Ubiquitinated: when eIF4E levels are low, hypophosphorylated form
CC is ubiquitinated by the BCR(KLHL25) complex, leading to its degradation
CC and serving as a homeostatic mechanism to maintain translation and
CC prevent eIF4E inhibition when eIF4E levels are low. Not ubiquitinated
CC when hyperphosphorylated (at Thr-37, Thr-46, Ser-65 and Thr-70) or
CC associated with eIF4E. {ECO:0000269|PubMed:22578813}.
CC -!- SIMILARITY: Belongs to the eIF4E-binding protein family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/EIF4EBP1ID40432ch8p12.html";
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DR EMBL; L36055; AAA62269.1; -; mRNA.
DR EMBL; AB044548; BAB18650.1; -; mRNA.
DR EMBL; BT007162; AAP35826.1; -; mRNA.
DR EMBL; CR456769; CAG33050.1; -; mRNA.
DR EMBL; AK312011; BAG34949.1; -; mRNA.
DR EMBL; CH471080; EAW63341.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63342.1; -; Genomic_DNA.
DR EMBL; BC004459; AAH04459.1; -; mRNA.
DR EMBL; BC058073; AAH58073.1; -; mRNA.
DR CCDS; CCDS6100.1; -.
DR PIR; S50866; S50866.
DR RefSeq; NP_004086.1; NM_004095.3.
DR PDB; 1EJ4; X-ray; 2.25 A; B=51-64.
DR PDB; 1EJH; X-ray; 2.20 A; E/F/G/H=54-66.
DR PDB; 1WKW; X-ray; 2.10 A; B=47-66.
DR PDB; 2JGB; X-ray; 1.70 A; B=51-67.
DR PDB; 2JGC; X-ray; 2.40 A; B=51-67.
DR PDB; 2V8W; X-ray; 2.30 A; B/F=51-64.
DR PDB; 2V8X; X-ray; 2.30 A; B/F=51-64.
DR PDB; 2V8Y; X-ray; 2.10 A; B/F=51-64.
DR PDB; 3HXG; X-ray; 2.10 A; C=51-67.
DR PDB; 3HXI; X-ray; 1.80 A; C=51-67.
DR PDB; 3M93; X-ray; 2.90 A; C=51-67.
DR PDB; 3M94; X-ray; 2.05 A; C=51-67.
DR PDB; 3U7X; X-ray; 2.10 A; C/D=47-66.
DR PDB; 4UED; X-ray; 1.75 A; B=50-83.
DR PDB; 5BXV; X-ray; 2.10 A; B/D=43-84.
DR PDB; 5EKV; X-ray; 3.61 A; B/D=51-64.
DR PDB; 5NVN; X-ray; 1.90 A; B/D=50-83.
DR PDB; 5WBJ; X-ray; 3.00 A; T=99-118.
DR PDB; 6BCU; EM; 3.43 A; X/Z=1-118.
DR PDB; 6BCX; EM; 3.00 A; X/Z=1-118.
DR PDBsum; 1EJ4; -.
DR PDBsum; 1EJH; -.
DR PDBsum; 1WKW; -.
DR PDBsum; 2JGB; -.
DR PDBsum; 2JGC; -.
DR PDBsum; 2V8W; -.
DR PDBsum; 2V8X; -.
DR PDBsum; 2V8Y; -.
DR PDBsum; 3HXG; -.
DR PDBsum; 3HXI; -.
DR PDBsum; 3M93; -.
DR PDBsum; 3M94; -.
DR PDBsum; 3U7X; -.
DR PDBsum; 4UED; -.
DR PDBsum; 5BXV; -.
DR PDBsum; 5EKV; -.
DR PDBsum; 5NVN; -.
DR PDBsum; 5WBJ; -.
DR PDBsum; 6BCU; -.
DR PDBsum; 6BCX; -.
DR AlphaFoldDB; Q13541; -.
DR BMRB; Q13541; -.
DR SMR; Q13541; -.
DR BioGRID; 108293; 81.
DR DIP; DIP-30944N; -.
DR ELM; Q13541; -.
DR IntAct; Q13541; 27.
DR MINT; Q13541; -.
DR STRING; 9606.ENSP00000340691; -.
DR ChEMBL; CHEMBL3351214; -.
DR GlyGen; Q13541; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q13541; -.
DR MetOSite; Q13541; -.
DR PhosphoSitePlus; Q13541; -.
DR BioMuta; EIF4EBP1; -.
DR DMDM; 34921508; -.
DR EPD; Q13541; -.
DR jPOST; Q13541; -.
DR MassIVE; Q13541; -.
DR MaxQB; Q13541; -.
DR PaxDb; Q13541; -.
DR PeptideAtlas; Q13541; -.
DR PRIDE; Q13541; -.
DR ProteomicsDB; 59525; -.
DR TopDownProteomics; Q13541; -.
DR Antibodypedia; 3558; 2081 antibodies from 48 providers.
DR DNASU; 1978; -.
DR Ensembl; ENST00000338825.5; ENSP00000340691.4; ENSG00000187840.5.
DR GeneID; 1978; -.
DR KEGG; hsa:1978; -.
DR MANE-Select; ENST00000338825.5; ENSP00000340691.4; NM_004095.4; NP_004086.1.
DR UCSC; uc003xks.4; human.
DR CTD; 1978; -.
DR DisGeNET; 1978; -.
DR GeneCards; EIF4EBP1; -.
DR HGNC; HGNC:3288; EIF4EBP1.
DR HPA; ENSG00000187840; Tissue enhanced (pancreas, salivary gland).
DR MIM; 602223; gene.
DR neXtProt; NX_Q13541; -.
DR OpenTargets; ENSG00000187840; -.
DR PharmGKB; PA27715; -.
DR VEuPathDB; HostDB:ENSG00000187840; -.
DR eggNOG; ENOG502S4SY; Eukaryota.
DR GeneTree; ENSGT00940000159932; -.
DR HOGENOM; CLU_111706_0_0_1; -.
DR InParanoid; Q13541; -.
DR OMA; PMMTRKI; -.
DR OrthoDB; 1597535at2759; -.
DR PhylomeDB; Q13541; -.
DR TreeFam; TF101530; -.
DR PathwayCommons; Q13541; -.
DR Reactome; R-HSA-166208; mTORC1-mediated signalling.
DR Reactome; R-HSA-72662; Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S.
DR SignaLink; Q13541; -.
DR SIGNOR; Q13541; -.
DR BioGRID-ORCS; 1978; 31 hits in 1077 CRISPR screens.
DR ChiTaRS; EIF4EBP1; human.
DR EvolutionaryTrace; Q13541; -.
DR GeneWiki; EIF4EBP1; -.
DR GenomeRNAi; 1978; -.
DR Pharos; Q13541; Tbio.
DR PRO; PR:Q13541; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q13541; protein.
DR Bgee; ENSG00000187840; Expressed in body of pancreas and 174 other tissues.
DR Genevisible; Q13541; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:AgBase.
DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; IDA:AgBase.
DR GO; GO:0030371; F:translation repressor activity; IDA:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0045947; P:negative regulation of translational initiation; IDA:UniProtKB.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0031929; P:TOR signaling; IDA:UniProtKB.
DR DisProt; DP00028; -.
DR IDEAL; IID00170; -.
DR InterPro; IPR008606; EIF4EBP.
DR InterPro; IPR037582; EIF4EBP1.
DR PANTHER; PTHR12669:SF14; PTHR12669:SF14; 1.
DR Pfam; PF05456; eIF_4EBP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Direct protein sequencing; Isopeptide bond;
KW Phosphoprotein; Protein synthesis inhibitor; Reference proteome;
KW Translation regulation; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:12665801,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..118
FT /note="Eukaryotic translation initiation factor 4E-binding
FT protein 1"
FT /id="PRO_0000190513"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 25..48
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 64..118
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 54..60
FT /note="YXXXXLphi motif"
FT /evidence="ECO:0000250|UniProtKB:P70445"
FT MOTIF 114..118
FT /note="TOS motif"
FT /evidence="ECO:0000269|PubMed:12747827"
FT COMPBIAS 1..15
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 34..48
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 79..97
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 98..118
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000269|PubMed:12665801,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 37
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:12747827,
FT ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:29750193,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 41
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 44
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q60876"
FT MOD_RES 46
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:12747827,
FT ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:29750193,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332"
FT MOD_RES 50
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18220336,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 54
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 65
FT /note="Phosphoserine; by DYRK2, MAPK1, MAPK3 and MTOR"
FT /evidence="ECO:0000269|PubMed:12588975,
FT ECO:0000269|PubMed:12747827, ECO:0000269|PubMed:22578813,
FT ECO:0000269|PubMed:25702871, ECO:0000269|PubMed:29750193,
FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 70
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:12747827,
FT ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:25702871,
FT ECO:0000269|PubMed:29750193, ECO:0007744|PubMed:18220336,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 77
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 96
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q60876"
FT MOD_RES 101
FT /note="Phosphoserine; by DYRK2"
FT /evidence="ECO:0000269|PubMed:12588975,
FT ECO:0007744|PubMed:18220336, ECO:0007744|PubMed:23186163"
FT MOD_RES 112
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:12588975,
FT ECO:0007744|PubMed:17525332, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT CROSSLNK 57
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000305|PubMed:22578813"
FT MUTAGEN 37
FT /note="T->A: Abolishes phosphorylation by MTOR and
FT increased ubiquitination by the BCR(KLHL25) complex; when
FT associated with A-46; A-65 and A-70."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 46
FT /note="T->A: Abolishes phosphorylation by MTOR and
FT increased ubiquitination by the BCR(KLHL25) complex; when
FT associated with A-37; A-65 and A-70."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 57
FT /note="K->R: Impaired ubiquitination by the BCR(KLHL25)
FT complex."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 59..60
FT /note="LM->AA: Abolishes eIF4E-binding. Increased
FT ubiquitination by the BCR(KLHL25) complex."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 65
FT /note="S->A: Abolishes phosphorylation by MTOR and
FT increased ubiquitination by the BCR(KLHL25) complex; when
FT associated with A-37; A-46 and A-70."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 69
FT /note="K->R: Does not affect ubiquitination by the
FT BCR(KLHL25) complex."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 70
FT /note="T->A: Abolishes phosphorylation by MTOR and
FT increased ubiquitination by the BCR(KLHL25) complex; when
FT associated with A-37; A-46 and A-65."
FT /evidence="ECO:0000269|PubMed:22578813"
FT MUTAGEN 105
FT /note="K->R: Does not affect ubiquitination by the
FT BCR(KLHL25) complex."
FT /evidence="ECO:0000269|PubMed:22578813"
FT HELIX 56..61
FT /evidence="ECO:0007829|PDB:2JGB"
FT HELIX 62..64
FT /evidence="ECO:0007829|PDB:2JGB"
FT HELIX 66..69
FT /evidence="ECO:0007829|PDB:4UED"
FT TURN 79..82
FT /evidence="ECO:0007829|PDB:4UED"
SQ SEQUENCE 118 AA; 12580 MW; 1682A6BA74132966 CRC64;
MSGGSSCSQT PSRAIPATRR VVLGDGVQLP PGDYSTTPGG TLFSTTPGGT RIIYDRKFLM
ECRNSPVTKT PPRDLPTIPG VTSPSSDEPP MEASQSHLRN SPEDKRAGGE ESQFEMDI
