Full text data of EIF4E
EIF4E
(EIF4EL1, EIF4F)
[Confidence: low (only semi-automatic identification from reviews)]
Eukaryotic translation initiation factor 4E; eIF-4E; eIF4E (eIF-4F 25 kDa subunit; mRNA cap-binding protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Eukaryotic translation initiation factor 4E; eIF-4E; eIF4E (eIF-4F 25 kDa subunit; mRNA cap-binding protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P06730
ID IF4E_HUMAN Reviewed; 217 AA.
AC P06730; B7Z6V1; D6RCQ6; Q96E95;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 2.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Eukaryotic translation initiation factor 4E;
DE Short=eIF-4E;
DE Short=eIF4E;
DE AltName: Full=eIF-4F 25 kDa subunit;
DE AltName: Full=mRNA cap-binding protein;
GN Name=EIF4E; Synonyms=EIF4EL1, EIF4F;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=3469651; DOI=10.1073/pnas.84.4.945;
RA Rychlik W., Domier L.L., Gardner P.R., Hellmann G.M., Rhoads R.E.;
RT "Amino acid sequence of the mRNA cap-binding protein from human
RT tissues.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:945-949(1987).
RN [2]
RP ERRATUM, AND SEQUENCE REVISION TO 108 AND 189.
RX PubMed=1736299; DOI=10.1073/pnas.89.3.1148a;
RA Rychlik W., Domier L.L., Gardner P.R., Hellmann G.M., Rhoads R.E.;
RL Proc. Natl. Acad. Sci. U.S.A. 89:1148-1148(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Small intestine;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Testis;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-214 (ISOFORM 2).
RC TISSUE=Myeloma;
RX PubMed=16341674; DOI=10.1007/s00335-005-0075-2;
RA Oh J.H., Yang J.O., Hahn Y., Kim M.R., Byun S.S., Jeon Y.J., Kim J.M.,
RA Song K.S., Noh S.M., Kim S., Yoo H.S., Kim Y.S., Kim N.S.;
RT "Transcriptome analysis of human gastric cancer.";
RL Mamm. Genome 16:942-954(2005).
RN [7]
RP PARTIAL PROTEIN SEQUENCE.
RX PubMed=1993647;
RA Marino M.W., Feld L.J., Jaffe E.A., Pfeffer L.M., Han Y.-M.,
RA Donner D.B.;
RT "Phosphorylation of the proto-oncogene product eukaryotic initiation
RT factor 4E is a common cellular response to tumor necrosis factor.";
RL J. Biol. Chem. 266:2685-2688(1991).
RN [8]
RP MUTAGENESIS OF TRP-102; GLU-103; ASP-104 AND GLU-105.
RX PubMed=1672854; DOI=10.1016/0014-5793(91)80294-D;
RA Ueda H., Iyo H., Doi M., Inoue M., Ishida T., Morioka H., Tanaka T.,
RA Nishikawa S., Uesugi S.;
RT "Combination of Trp and Glu residues for recognition of mRNA cap
RT structure. Analysis of m7G base recognition site of human cap binding
RT protein (IF-4E) by site-directed mutagenesis.";
RL FEBS Lett. 280:207-210(1991).
RN [9]
RP PHOSPHORYLATION.
RX PubMed=3112145;
RA Rychlik W., Russ M.A., Rhoads R.E.;
RT "Phosphorylation site of eukaryotic initiation factor 4E.";
RL J. Biol. Chem. 262:10434-10437(1987).
RN [10]
RP PHOSPHORYLATION, AND MUTAGENESIS OF SER-53.
RX PubMed=8505316;
RA Kaufman R.J., Murtha-Riel P., Pittman D.D., Davies M.V.;
RT "Characterization of wild-type and Ser53 mutant eukaryotic initiation
RT factor 4E overexpression in mammalian cells.";
RL J. Biol. Chem. 268:11902-11909(1993).
RN [11]
RP PHOSPHORYLATION, AND MUTAGENESIS OF SER-53.
RX PubMed=7590282; DOI=10.1016/0378-1119(95)00302-M;
RA Zhang Y., Klein H.L., Schneider R.J.;
RT "Role of Ser-53 phosphorylation in the activity of human translation
RT initiation factor eIF-4E in mammalian and yeast cells.";
RL Gene 163:283-288(1995).
RN [12]
RP PHOSPHORYLATION AT SER-209.
RX PubMed=7782323; DOI=10.1074/jbc.270.24.14597;
RA Joshi B., Cai A.L., Keiper B.D., Minich W.B., Mendez R., Beach C.M.,
RA Stepinski J., Stolarski R., Darzynkiewicz E., Rhoads R.E.;
RT "Phosphorylation of eukaryotic protein synthesis initiation factor 4E
RT at Ser-209.";
RL J. Biol. Chem. 270:14597-14603(1995).
RN [13]
RP PHOSPHORYLATION AT SER-209.
RX PubMed=7665584; DOI=10.1074/jbc.270.37.21684;
RA Flynn A., Proud C.G.;
RT "Serine 209, not serine 53, is the major site of phosphorylation in
RT initiation factor eIF-4E in serum-treated Chinese hamster ovary
RT cells.";
RL J. Biol. Chem. 270:21684-21688(1995).
RN [14]
RP INTERACTION WITH EIF4G AND EIF4EBP1.
RX PubMed=8521827;
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-
RT 4E.";
RL EMBO J. 14:5701-5709(1995).
RN [15]
RP INTERACTION WITH EIF4ENIF1.
RC TISSUE=Fetal brain, and Placenta;
RX PubMed=10856257; DOI=10.1093/emboj/19.12.3142;
RA Dostie J., Ferraiuolo M., Pause A., Adam S.A., Sonenberg N.;
RT "A novel shuttling protein, 4E-T, mediates the nuclear import of the
RT mRNA 5' cap-binding protein, eIF4E.";
RL EMBO J. 19:3142-3156(2000).
RN [16]
RP PHOSPHORYLATION BY MKNK1.
RX PubMed=9878069; DOI=10.1093/emboj/18.1.270;
RA Pyronnet S., Imataka H., Gingras A.-C., Fukunaga R., Hunter T.,
RA Sonenberg N.;
RT "Human eukaryotic translation initiation factor 4G (eIF4G) recruits
RT mnk1 to phosphorylate eIF4E.";
RL EMBO J. 18:270-279(1999).
RN [17]
RP INTERACTION WITH EIF4A1 AND EIF4A2.
RX PubMed=11408474; DOI=10.1074/jbc.C100284200;
RA Li W., Belsham G.J., Proud C.G.;
RT "Eukaryotic initiation factors 4A (eIF4A) and 4G (eIF4G) mutually
RT interact in a 1:1 ratio in vivo.";
RL J. Biol. Chem. 276:29111-29115(2001).
RN [18]
RP PHOSPHORYLATION AT SER-209 BY MKNK2.
RX PubMed=11154262; DOI=10.1128/MCB.21.3.743-754.2001;
RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2
RT is a eukaryotic initiation factor 4E kinase with high levels of basal
RT activity in mammalian cells.";
RL Mol. Cell. Biol. 21:743-754(2001).
RN [19]
RP INTERACTION WITH MKNK2.
RX PubMed=12897141; DOI=10.1128/MCB.23.16.5692-5705.2003;
RA Scheper G.C., Parra J.L., Wilson M., Van Kollenburg B.,
RA Vertegaal A.C.O., Han Z.-G., Proud C.G.;
RT "The N and C termini of the splice variants of the human mitogen-
RT activated protein kinase-interacting kinase Mnk2 determine activity
RT and localization.";
RL Mol. Cell. Biol. 23:5692-5705(2003).
RN [20]
RP INTERACTION WITH APOBEC3G.
RX PubMed=16699599; DOI=10.1371/journal.ppat.0020041;
RA Wichroski M.J., Robb G.B., Rana T.M.;
RT "Human retroviral host restriction factors APOBEC3G and APOBEC3F
RT localize to mRNA processing bodies.";
RL PLoS Pathog. 2:E41-E41(2006).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [22]
RP INVOLVEMENT IN AUTS19, AND CHROMOSOMAL TRANSLOCATION.
RX PubMed=19556253; DOI=10.1136/jmg.2009.066852;
RA Neves-Pereira M., Mueller B., Massie D., Williams J.H., O'Brien P.C.,
RA Hughes A., Shen S.B., Clair D.S., Miedzybrodzka Z.;
RT "Deregulation of EIF4E: a novel mechanism for autism.";
RL J. Med. Genet. 46:759-765(2009).
RN [23]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH LIMD1; WTIP AND AJUBA.
RX PubMed=20616046; DOI=10.1073/pnas.0914987107;
RA James V., Zhang Y., Foxler D.E., de Moor C.H., Kong Y.W., Webb T.M.,
RA Self T.J., Feng Y., Lagos D., Chu C.Y., Rana T.M., Morley S.J.,
RA Longmore G.D., Bushell M., Sharp T.V.;
RT "LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
RT microRNA-mediated gene silencing.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:12499-12504(2010).
RN [24]
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.,
RA Buerckstuemmer T., 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 [25]
RP FUNCTION, AND MUTAGENESIS OF TRP-73.
RX PubMed=22578813; DOI=10.1016/j.molcel.2012.04.004;
RA Yanagiya A., Suyama E., Adachi H., Svitkin Y.V., Aza-Blanc P.,
RA Imataka H., 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 [26]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH MRNA CAP
RP ANALOGS.
RX PubMed=11879179; DOI=10.1042/0264-6021:3620539;
RA Tomoo K., Shen X., Okabe K., Nozoe Y., Fukuhara S., Morino S.,
RA Ishida T., Taniguchi T., Hasegawa H., Terashima A., Sasaki M.,
RA Katsuya Y., Kitamura K., Miyoshi H., Ishikawa M., Miura K.;
RT "Crystal structures of 7-methylguanosine 5'-triphosphate (m(7)GTP)-
RT and P(1)-7-methylguanosine-P(3)-adenosine-5',5'-triphosphate
RT (m(7)GpppA)-bound human full-length eukaryotic initiation factor 4E:
RT biological importance of the C-terminal flexible region.";
RL Biochem. J. 362:539-544(2002).
RN [27]
RP STRUCTURE BY NMR IN COMPLEX WITH EIF4G3 AND MRNA CAP ANALOGS.
RX PubMed=12975586; DOI=10.1023/A:1025442322316;
RA Miura T., Shiratori Y., Shimma N.;
RT "Backbone resonance assignment of human eukaryotic translation
RT initiation factor 4E (eIF4E) in complex with 7-methylguanosine
RT diphosphate (m7GDP) and a 17-amino acid peptide derived from human
RT eIF4GII.";
RL J. Biomol. NMR 27:279-280(2003).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 27-217 IN COMPLEX WITH MRNA
RP CAP ANALOG AND EIF4EBP1, FUNCTION, AND INTERACTION WITH EIF4EBP1;
RP EIF4EBP2 AND EIF4EBP3.
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
RT initiation factor 4E by 4E-binding protein, studied by spectroscopic,
RT X-ray crystal structural, and molecular dynamics simulation methods.";
RL Biochim. Biophys. Acta 1753:191-208(2005).
RN [29]
RP STRUCTURE BY NMR, CLEAVAGE OF INITIATOR METHIONINE, MASS SPECTROMETRY,
RP AND MUTAGENESIS OF LYS-119.
RX PubMed=17036047; DOI=10.1038/sj.emboj.7601380;
RA Volpon L., Osborne M.J., Topisirovic I., Siddiqui N., Borden K.L.B.;
RT "Cap-free structure of eIF4E suggests a basis for conformational
RT regulation by its ligands.";
RL EMBO J. 25:5138-5149(2006).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH MRNA CAP
RP ANALOGS, AND MASS SPECTROMETRY.
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
RT with N7-alkylated cap derivatives.";
RL J. Mol. Biol. 372:7-15(2007).
CC -!- FUNCTION: Recognizes and binds the 7-methylguanosine-containing
CC mRNA cap during an early step in the initiation of protein
CC synthesis and facilitates ribosome binding by inducing the
CC unwinding of the mRNAs secondary structures. Component of the
CC CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates
CC translational repression. In the CYFIP1-EIF4E-FMR1 complex this
CC subunit mediates the binding to the mRNA cap.
CC -!- SUBUNIT: eIF4F is a multi-subunit complex, the composition of
CC which varies with external and internal environmental conditions.
CC It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3. EIF4E
CC is also known to interact with other partners. The interaction
CC with EIF4ENIF1 mediates the import into the nucleus.
CC Hypophosphorylated EIF4EBP1, EIF4EBP2 and EIF4EBP3 compete with
CC EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-
CC kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes
CC dissociation of the complex allowing EIF4G1/EIF4G3 to bind and
CC consequent initiation of translation. Rapamycin can attenuate
CC insulin stimulation, mediated by FKBPs. Interacts mutually
CC exclusive with EIF4A1 or EIF4A2. Interacts with NGDN and PIWIL2.
CC Component of the CYFIP1-EIF4E-FMR1 complex composed of CYFIP,
CC EIF4E and FMR1. Interacts directly with CYFIP1 (By similarity).
CC Interacts with Lassa virus Z protein. Binds to MKNK2 in nucleus.
CC Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3G in
CC an RNA-dependent manner.
CC -!- INTERACTION:
CC Q13541:EIF4EBP1; NbExp=8; IntAct=EBI-73440, EBI-74090;
CC O60516:EIF4EBP3; NbExp=2; IntAct=EBI-73440, EBI-746950;
CC Q9NRA8:EIF4ENIF1; NbExp=6; IntAct=EBI-73440, EBI-301024;
CC Q04637:EIF4G1; NbExp=2; IntAct=EBI-73440, EBI-73711;
CC Q04743:EMX2; NbExp=4; IntAct=EBI-73440, EBI-399831;
CC Q8TEQ6:GEMIN5; NbExp=3; IntAct=EBI-73440, EBI-443630;
CC P42704:LRPPRC; NbExp=6; IntAct=EBI-73440, EBI-1050853;
CC P63165:SUMO1; NbExp=5; IntAct=EBI-73440, EBI-80140;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, P-body.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P06730-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P06730-2; Sequence=VSP_042014;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P06730-3; Sequence=VSP_043591;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation increases the ability of the protein to bind
CC to mRNA caps and to form the eIF4F complex.
CC -!- MASS SPECTROMETRY: Mass=24964.3; Method=Electrospray; Range=2-217;
CC Source=PubMed:17036047;
CC -!- MASS SPECTROMETRY: Mass=24960; Method=Electrospray; Range=2-217;
CC Source=PubMed:17631896;
CC -!- DISEASE: Autism 19 (AUTS19) [MIM:615091]: A complex
CC multifactorial, pervasive developmental disorder characterized by
CC impairments in reciprocal social interaction and communication,
CC restricted and stereotyped patterns of interests and activities,
CC and the presence of developmental abnormalities by 3 years of age.
CC Most individuals with autism also manifest moderate mental
CC retardation. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry. A
CC heterozygous single-nucleotide insertion has been found in
CC families affected by autism. The variant results in increased
CC promoter activity and is involved in disease pathogenesis through
CC EIF4E deregulation (PubMed:19556253).
CC -!- DISEASE: Note=A chromosomal aberration involving EIF4E has been
CC found in a patient with classic autism. Translocation
CC t(45)(q23q31.3). The breakpoint on chromosome 4 is located 56 kb
CC downstream of EIF4E (PubMed:19556253).
CC -!- SIMILARITY: Belongs to the eukaryotic initiation factor 4E family.
CC -!- CAUTION: Was originally thought to be phosphorylated on Ser-53
CC (PubMed:3112145); this was later shown to be wrong
CC (PubMed:7665584).
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/EIF4EID40431ch4q23.html";
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DR EMBL; M15353; AAC13647.1; -; mRNA.
DR EMBL; AK300982; BAH13387.1; -; mRNA.
DR EMBL; AC019131; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093836; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC012611; AAH12611.1; -; mRNA.
DR EMBL; BC035166; AAH35166.1; -; mRNA.
DR EMBL; BC043226; AAH43226.1; -; mRNA.
DR EMBL; BM849222; -; NOT_ANNOTATED_CDS; mRNA.
DR PIR; A26411; A26411.
DR RefSeq; NP_001124150.1; NM_001130678.1.
DR RefSeq; NP_001124151.1; NM_001130679.1.
DR RefSeq; NP_001959.1; NM_001968.3.
DR UniGene; Hs.249718; -.
DR PDB; 1IPB; X-ray; 2.00 A; A=1-217.
DR PDB; 1IPC; X-ray; 2.00 A; A=1-217.
DR PDB; 1WKW; X-ray; 2.10 A; A=27-217.
DR PDB; 2GPQ; NMR; -; A=1-217.
DR PDB; 2V8W; X-ray; 2.30 A; A/E=1-217.
DR PDB; 2V8X; X-ray; 2.30 A; A/E=1-217.
DR PDB; 2V8Y; X-ray; 2.10 A; A/E=1-217.
DR PDB; 2W97; X-ray; 2.29 A; A/B=1-217.
DR PDB; 3AM7; X-ray; 2.20 A; A=27-217.
DR PDB; 3TF2; X-ray; 2.10 A; A/B/C/D=1-217.
DR PDB; 3U7X; X-ray; 2.10 A; A/B=1-217.
DR PDB; 4AZA; X-ray; 2.16 A; A/C=1-217.
DR PDB; 4DT6; X-ray; 2.60 A; A=1-217.
DR PDB; 4DUM; X-ray; 2.95 A; A=1-217.
DR PDBsum; 1IPB; -.
DR PDBsum; 1IPC; -.
DR PDBsum; 1WKW; -.
DR PDBsum; 2GPQ; -.
DR PDBsum; 2V8W; -.
DR PDBsum; 2V8X; -.
DR PDBsum; 2V8Y; -.
DR PDBsum; 2W97; -.
DR PDBsum; 3AM7; -.
DR PDBsum; 3TF2; -.
DR PDBsum; 3U7X; -.
DR PDBsum; 4AZA; -.
DR PDBsum; 4DT6; -.
DR PDBsum; 4DUM; -.
DR ProteinModelPortal; P06730; -.
DR SMR; P06730; 1-217.
DR DIP; DIP-22N; -.
DR IntAct; P06730; 30.
DR MINT; MINT-85626; -.
DR STRING; 9606.ENSP00000280892; -.
DR BindingDB; P06730; -.
DR ChEMBL; CHEMBL4848; -.
DR PhosphoSite; P06730; -.
DR DMDM; 1352435; -.
DR OGP; P06730; -.
DR REPRODUCTION-2DPAGE; IPI00027485; -.
DR PaxDb; P06730; -.
DR PRIDE; P06730; -.
DR DNASU; 1977; -.
DR Ensembl; ENST00000280892; ENSP00000280892; ENSG00000151247.
DR Ensembl; ENST00000450253; ENSP00000389624; ENSG00000151247.
DR Ensembl; ENST00000505992; ENSP00000425561; ENSG00000151247.
DR GeneID; 1977; -.
DR KEGG; hsa:1977; -.
DR UCSC; uc003hue.2; human.
DR CTD; 1977; -.
DR GeneCards; GC04M099799; -.
DR H-InvDB; HIX0039231; -.
DR HGNC; HGNC:3287; EIF4E.
DR HPA; CAB004077; -.
DR HPA; CAB016316; -.
DR MIM; 133440; gene.
DR MIM; 615091; phenotype.
DR neXtProt; NX_P06730; -.
DR Orphanet; 106; Autism.
DR PharmGKB; PA27714; -.
DR eggNOG; COG5053; -.
DR HOGENOM; HOG000186751; -.
DR HOVERGEN; HBG006130; -.
DR KO; K03259; -.
DR OMA; NDENTAP; -.
DR OrthoDB; EOG7QRQVM; -.
DR PhylomeDB; P06730; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_1675; mRNA Processing.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P06730; -.
DR ChiTaRS; EIF4E; human.
DR EvolutionaryTrace; P06730; -.
DR GeneWiki; EIF4E; -.
DR GenomeRNAi; 1977; -.
DR NextBio; 7999; -.
DR PRO; PR:P06730; -.
DR ArrayExpress; P06730; -.
DR Bgee; P06730; -.
DR CleanEx; HS_EIF4E; -.
DR Genevestigator; P06730; -.
DR GO; GO:0033391; C:chromatoid body; IEA:Ensembl.
DR GO; GO:0000932; C:cytoplasmic mRNA processing body; IDA:MGI.
DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016281; C:eukaryotic translation initiation factor 4F complex; IDA:UniProtKB.
DR GO; GO:0005845; C:mRNA cap binding complex; IDA:UniProtKB.
DR GO; GO:0016442; C:RISC complex; IDA:MGI.
DR GO; GO:0000339; F:RNA cap binding; TAS:ProtInc.
DR GO; GO:0003743; F:translation initiation factor activity; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0006406; P:mRNA export from nucleus; TAS:Reactome.
DR GO; GO:0000289; P:nuclear-transcribed mRNA poly(A) tail shortening; TAS:Reactome.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0006417; P:regulation of translation; IDA:UniProtKB.
DR Gene3D; 3.30.760.10; -; 1.
DR InterPro; IPR023398; TIF_eIF4e-like_dom.
DR InterPro; IPR001040; TIF_eIF_4E.
DR InterPro; IPR019770; TIF_eIF_4E_CS.
DR PANTHER; PTHR11960; PTHR11960; 1.
DR Pfam; PF01652; IF4E; 1.
DR SUPFAM; SSF55418; SSF55418; 1.
DR PROSITE; PS00813; IF4E; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Chromosomal rearrangement; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Host-virus interaction; Initiation factor;
KW Phosphoprotein; Protein biosynthesis; Reference proteome; RNA-binding;
KW Translation regulation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 217 Eukaryotic translation initiation factor
FT 4E.
FT /FTId=PRO_0000193634.
FT REGION 37 40 EIF4EBP1/2/3 binding.
FT REGION 56 57 7-methylguanosine-containing mRNA cap
FT binding.
FT REGION 73 77 EIF4EBP1/2/3 binding.
FT REGION 102 103 7-methylguanosine-containing mRNA cap
FT binding.
FT REGION 132 139 EIF4EBP1/2/3 binding.
FT REGION 157 162 7-methylguanosine-containing mRNA cap
FT binding.
FT REGION 205 207 7-methylguanosine-containing mRNA cap
FT binding.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 209 209 Phosphoserine; by PKC and MKNK2.
FT VAR_SEQ 1 6 MATVEP -> MLDLTSRGQVGTSRRMAEAACSAHFL (in
FT isoform 3).
FT /FTId=VSP_043591.
FT VAR_SEQ 133 133 T -> TRWDLAMLPRLVSNFWPQVILPLQPPKVLELQ (in
FT isoform 2).
FT /FTId=VSP_042014.
FT MUTAGEN 53 53 S->A,D: No effect on phosphorylation
FT level nor incorporation into eIF4F
FT complex.
FT MUTAGEN 73 73 W->A: Abolishes binding to EIF4EBP1.
FT MUTAGEN 102 102 W->L: Decrease in mRNA cap binding; when
FT associated with A-105.
FT MUTAGEN 103 103 E->A: No effect.
FT MUTAGEN 104 104 D->A: No effect.
FT MUTAGEN 105 105 E->A: Decrease in mRNA cap binding; when
FT associated with L-102.
FT MUTAGEN 119 119 K->A: Higher affinity for EIF4G1.
FT CONFLICT 127 127 D -> N (in Ref. 5; AAH12611).
FT HELIX 31 33
FT STRAND 38 48
FT STRAND 52 54
FT HELIX 57 59
FT STRAND 60 68
FT HELIX 69 78
FT HELIX 82 84
FT STRAND 90 95
FT STRAND 100 103
FT TURN 105 109
FT STRAND 111 116
FT HELIX 121 124
FT HELIX 126 138
FT TURN 139 142
FT HELIX 143 148
FT STRAND 149 155
FT STRAND 162 168
FT HELIX 173 187
FT TURN 188 192
FT STRAND 196 199
FT HELIX 200 202
FT STRAND 206 208
FT STRAND 214 216
SQ SEQUENCE 217 AA; 25097 MW; B869B8DE615E699D CRC64;
MATVEPETTP TPNPPTTEEE KTESNQEVAN PEHYIKHPLQ NRWALWFFKN DKSKTWQANL
RLISKFDTVE DFWALYNHIQ LSSNLMPGCD YSLFKDGIEP MWEDEKNKRG GRWLITLNKQ
QRRSDLDRFW LETLLCLIGE SFDDYSDDVC GAVVNVRAKG DKIAIWTTEC ENREAVTHIG
RVYKERLGLP PKIVIGYQSH ADTATKSGST TKNRFVV
//
ID IF4E_HUMAN Reviewed; 217 AA.
AC P06730; B7Z6V1; D6RCQ6; Q96E95;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 2.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Eukaryotic translation initiation factor 4E;
DE Short=eIF-4E;
DE Short=eIF4E;
DE AltName: Full=eIF-4F 25 kDa subunit;
DE AltName: Full=mRNA cap-binding protein;
GN Name=EIF4E; Synonyms=EIF4EL1, EIF4F;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=3469651; DOI=10.1073/pnas.84.4.945;
RA Rychlik W., Domier L.L., Gardner P.R., Hellmann G.M., Rhoads R.E.;
RT "Amino acid sequence of the mRNA cap-binding protein from human
RT tissues.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:945-949(1987).
RN [2]
RP ERRATUM, AND SEQUENCE REVISION TO 108 AND 189.
RX PubMed=1736299; DOI=10.1073/pnas.89.3.1148a;
RA Rychlik W., Domier L.L., Gardner P.R., Hellmann G.M., Rhoads R.E.;
RL Proc. Natl. Acad. Sci. U.S.A. 89:1148-1148(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Small intestine;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Testis;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-214 (ISOFORM 2).
RC TISSUE=Myeloma;
RX PubMed=16341674; DOI=10.1007/s00335-005-0075-2;
RA Oh J.H., Yang J.O., Hahn Y., Kim M.R., Byun S.S., Jeon Y.J., Kim J.M.,
RA Song K.S., Noh S.M., Kim S., Yoo H.S., Kim Y.S., Kim N.S.;
RT "Transcriptome analysis of human gastric cancer.";
RL Mamm. Genome 16:942-954(2005).
RN [7]
RP PARTIAL PROTEIN SEQUENCE.
RX PubMed=1993647;
RA Marino M.W., Feld L.J., Jaffe E.A., Pfeffer L.M., Han Y.-M.,
RA Donner D.B.;
RT "Phosphorylation of the proto-oncogene product eukaryotic initiation
RT factor 4E is a common cellular response to tumor necrosis factor.";
RL J. Biol. Chem. 266:2685-2688(1991).
RN [8]
RP MUTAGENESIS OF TRP-102; GLU-103; ASP-104 AND GLU-105.
RX PubMed=1672854; DOI=10.1016/0014-5793(91)80294-D;
RA Ueda H., Iyo H., Doi M., Inoue M., Ishida T., Morioka H., Tanaka T.,
RA Nishikawa S., Uesugi S.;
RT "Combination of Trp and Glu residues for recognition of mRNA cap
RT structure. Analysis of m7G base recognition site of human cap binding
RT protein (IF-4E) by site-directed mutagenesis.";
RL FEBS Lett. 280:207-210(1991).
RN [9]
RP PHOSPHORYLATION.
RX PubMed=3112145;
RA Rychlik W., Russ M.A., Rhoads R.E.;
RT "Phosphorylation site of eukaryotic initiation factor 4E.";
RL J. Biol. Chem. 262:10434-10437(1987).
RN [10]
RP PHOSPHORYLATION, AND MUTAGENESIS OF SER-53.
RX PubMed=8505316;
RA Kaufman R.J., Murtha-Riel P., Pittman D.D., Davies M.V.;
RT "Characterization of wild-type and Ser53 mutant eukaryotic initiation
RT factor 4E overexpression in mammalian cells.";
RL J. Biol. Chem. 268:11902-11909(1993).
RN [11]
RP PHOSPHORYLATION, AND MUTAGENESIS OF SER-53.
RX PubMed=7590282; DOI=10.1016/0378-1119(95)00302-M;
RA Zhang Y., Klein H.L., Schneider R.J.;
RT "Role of Ser-53 phosphorylation in the activity of human translation
RT initiation factor eIF-4E in mammalian and yeast cells.";
RL Gene 163:283-288(1995).
RN [12]
RP PHOSPHORYLATION AT SER-209.
RX PubMed=7782323; DOI=10.1074/jbc.270.24.14597;
RA Joshi B., Cai A.L., Keiper B.D., Minich W.B., Mendez R., Beach C.M.,
RA Stepinski J., Stolarski R., Darzynkiewicz E., Rhoads R.E.;
RT "Phosphorylation of eukaryotic protein synthesis initiation factor 4E
RT at Ser-209.";
RL J. Biol. Chem. 270:14597-14603(1995).
RN [13]
RP PHOSPHORYLATION AT SER-209.
RX PubMed=7665584; DOI=10.1074/jbc.270.37.21684;
RA Flynn A., Proud C.G.;
RT "Serine 209, not serine 53, is the major site of phosphorylation in
RT initiation factor eIF-4E in serum-treated Chinese hamster ovary
RT cells.";
RL J. Biol. Chem. 270:21684-21688(1995).
RN [14]
RP INTERACTION WITH EIF4G AND EIF4EBP1.
RX PubMed=8521827;
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-
RT 4E.";
RL EMBO J. 14:5701-5709(1995).
RN [15]
RP INTERACTION WITH EIF4ENIF1.
RC TISSUE=Fetal brain, and Placenta;
RX PubMed=10856257; DOI=10.1093/emboj/19.12.3142;
RA Dostie J., Ferraiuolo M., Pause A., Adam S.A., Sonenberg N.;
RT "A novel shuttling protein, 4E-T, mediates the nuclear import of the
RT mRNA 5' cap-binding protein, eIF4E.";
RL EMBO J. 19:3142-3156(2000).
RN [16]
RP PHOSPHORYLATION BY MKNK1.
RX PubMed=9878069; DOI=10.1093/emboj/18.1.270;
RA Pyronnet S., Imataka H., Gingras A.-C., Fukunaga R., Hunter T.,
RA Sonenberg N.;
RT "Human eukaryotic translation initiation factor 4G (eIF4G) recruits
RT mnk1 to phosphorylate eIF4E.";
RL EMBO J. 18:270-279(1999).
RN [17]
RP INTERACTION WITH EIF4A1 AND EIF4A2.
RX PubMed=11408474; DOI=10.1074/jbc.C100284200;
RA Li W., Belsham G.J., Proud C.G.;
RT "Eukaryotic initiation factors 4A (eIF4A) and 4G (eIF4G) mutually
RT interact in a 1:1 ratio in vivo.";
RL J. Biol. Chem. 276:29111-29115(2001).
RN [18]
RP PHOSPHORYLATION AT SER-209 BY MKNK2.
RX PubMed=11154262; DOI=10.1128/MCB.21.3.743-754.2001;
RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2
RT is a eukaryotic initiation factor 4E kinase with high levels of basal
RT activity in mammalian cells.";
RL Mol. Cell. Biol. 21:743-754(2001).
RN [19]
RP INTERACTION WITH MKNK2.
RX PubMed=12897141; DOI=10.1128/MCB.23.16.5692-5705.2003;
RA Scheper G.C., Parra J.L., Wilson M., Van Kollenburg B.,
RA Vertegaal A.C.O., Han Z.-G., Proud C.G.;
RT "The N and C termini of the splice variants of the human mitogen-
RT activated protein kinase-interacting kinase Mnk2 determine activity
RT and localization.";
RL Mol. Cell. Biol. 23:5692-5705(2003).
RN [20]
RP INTERACTION WITH APOBEC3G.
RX PubMed=16699599; DOI=10.1371/journal.ppat.0020041;
RA Wichroski M.J., Robb G.B., Rana T.M.;
RT "Human retroviral host restriction factors APOBEC3G and APOBEC3F
RT localize to mRNA processing bodies.";
RL PLoS Pathog. 2:E41-E41(2006).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [22]
RP INVOLVEMENT IN AUTS19, AND CHROMOSOMAL TRANSLOCATION.
RX PubMed=19556253; DOI=10.1136/jmg.2009.066852;
RA Neves-Pereira M., Mueller B., Massie D., Williams J.H., O'Brien P.C.,
RA Hughes A., Shen S.B., Clair D.S., Miedzybrodzka Z.;
RT "Deregulation of EIF4E: a novel mechanism for autism.";
RL J. Med. Genet. 46:759-765(2009).
RN [23]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH LIMD1; WTIP AND AJUBA.
RX PubMed=20616046; DOI=10.1073/pnas.0914987107;
RA James V., Zhang Y., Foxler D.E., de Moor C.H., Kong Y.W., Webb T.M.,
RA Self T.J., Feng Y., Lagos D., Chu C.Y., Rana T.M., Morley S.J.,
RA Longmore G.D., Bushell M., Sharp T.V.;
RT "LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
RT microRNA-mediated gene silencing.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:12499-12504(2010).
RN [24]
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.,
RA Buerckstuemmer T., 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 [25]
RP FUNCTION, AND MUTAGENESIS OF TRP-73.
RX PubMed=22578813; DOI=10.1016/j.molcel.2012.04.004;
RA Yanagiya A., Suyama E., Adachi H., Svitkin Y.V., Aza-Blanc P.,
RA Imataka H., 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 [26]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH MRNA CAP
RP ANALOGS.
RX PubMed=11879179; DOI=10.1042/0264-6021:3620539;
RA Tomoo K., Shen X., Okabe K., Nozoe Y., Fukuhara S., Morino S.,
RA Ishida T., Taniguchi T., Hasegawa H., Terashima A., Sasaki M.,
RA Katsuya Y., Kitamura K., Miyoshi H., Ishikawa M., Miura K.;
RT "Crystal structures of 7-methylguanosine 5'-triphosphate (m(7)GTP)-
RT and P(1)-7-methylguanosine-P(3)-adenosine-5',5'-triphosphate
RT (m(7)GpppA)-bound human full-length eukaryotic initiation factor 4E:
RT biological importance of the C-terminal flexible region.";
RL Biochem. J. 362:539-544(2002).
RN [27]
RP STRUCTURE BY NMR IN COMPLEX WITH EIF4G3 AND MRNA CAP ANALOGS.
RX PubMed=12975586; DOI=10.1023/A:1025442322316;
RA Miura T., Shiratori Y., Shimma N.;
RT "Backbone resonance assignment of human eukaryotic translation
RT initiation factor 4E (eIF4E) in complex with 7-methylguanosine
RT diphosphate (m7GDP) and a 17-amino acid peptide derived from human
RT eIF4GII.";
RL J. Biomol. NMR 27:279-280(2003).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 27-217 IN COMPLEX WITH MRNA
RP CAP ANALOG AND EIF4EBP1, FUNCTION, AND INTERACTION WITH EIF4EBP1;
RP EIF4EBP2 AND EIF4EBP3.
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
RT initiation factor 4E by 4E-binding protein, studied by spectroscopic,
RT X-ray crystal structural, and molecular dynamics simulation methods.";
RL Biochim. Biophys. Acta 1753:191-208(2005).
RN [29]
RP STRUCTURE BY NMR, CLEAVAGE OF INITIATOR METHIONINE, MASS SPECTROMETRY,
RP AND MUTAGENESIS OF LYS-119.
RX PubMed=17036047; DOI=10.1038/sj.emboj.7601380;
RA Volpon L., Osborne M.J., Topisirovic I., Siddiqui N., Borden K.L.B.;
RT "Cap-free structure of eIF4E suggests a basis for conformational
RT regulation by its ligands.";
RL EMBO J. 25:5138-5149(2006).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH MRNA CAP
RP ANALOGS, AND MASS SPECTROMETRY.
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
RT with N7-alkylated cap derivatives.";
RL J. Mol. Biol. 372:7-15(2007).
CC -!- FUNCTION: Recognizes and binds the 7-methylguanosine-containing
CC mRNA cap during an early step in the initiation of protein
CC synthesis and facilitates ribosome binding by inducing the
CC unwinding of the mRNAs secondary structures. Component of the
CC CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates
CC translational repression. In the CYFIP1-EIF4E-FMR1 complex this
CC subunit mediates the binding to the mRNA cap.
CC -!- SUBUNIT: eIF4F is a multi-subunit complex, the composition of
CC which varies with external and internal environmental conditions.
CC It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3. EIF4E
CC is also known to interact with other partners. The interaction
CC with EIF4ENIF1 mediates the import into the nucleus.
CC Hypophosphorylated EIF4EBP1, EIF4EBP2 and EIF4EBP3 compete with
CC EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-
CC kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes
CC dissociation of the complex allowing EIF4G1/EIF4G3 to bind and
CC consequent initiation of translation. Rapamycin can attenuate
CC insulin stimulation, mediated by FKBPs. Interacts mutually
CC exclusive with EIF4A1 or EIF4A2. Interacts with NGDN and PIWIL2.
CC Component of the CYFIP1-EIF4E-FMR1 complex composed of CYFIP,
CC EIF4E and FMR1. Interacts directly with CYFIP1 (By similarity).
CC Interacts with Lassa virus Z protein. Binds to MKNK2 in nucleus.
CC Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3G in
CC an RNA-dependent manner.
CC -!- INTERACTION:
CC Q13541:EIF4EBP1; NbExp=8; IntAct=EBI-73440, EBI-74090;
CC O60516:EIF4EBP3; NbExp=2; IntAct=EBI-73440, EBI-746950;
CC Q9NRA8:EIF4ENIF1; NbExp=6; IntAct=EBI-73440, EBI-301024;
CC Q04637:EIF4G1; NbExp=2; IntAct=EBI-73440, EBI-73711;
CC Q04743:EMX2; NbExp=4; IntAct=EBI-73440, EBI-399831;
CC Q8TEQ6:GEMIN5; NbExp=3; IntAct=EBI-73440, EBI-443630;
CC P42704:LRPPRC; NbExp=6; IntAct=EBI-73440, EBI-1050853;
CC P63165:SUMO1; NbExp=5; IntAct=EBI-73440, EBI-80140;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, P-body.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P06730-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P06730-2; Sequence=VSP_042014;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P06730-3; Sequence=VSP_043591;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation increases the ability of the protein to bind
CC to mRNA caps and to form the eIF4F complex.
CC -!- MASS SPECTROMETRY: Mass=24964.3; Method=Electrospray; Range=2-217;
CC Source=PubMed:17036047;
CC -!- MASS SPECTROMETRY: Mass=24960; Method=Electrospray; Range=2-217;
CC Source=PubMed:17631896;
CC -!- DISEASE: Autism 19 (AUTS19) [MIM:615091]: A complex
CC multifactorial, pervasive developmental disorder characterized by
CC impairments in reciprocal social interaction and communication,
CC restricted and stereotyped patterns of interests and activities,
CC and the presence of developmental abnormalities by 3 years of age.
CC Most individuals with autism also manifest moderate mental
CC retardation. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry. A
CC heterozygous single-nucleotide insertion has been found in
CC families affected by autism. The variant results in increased
CC promoter activity and is involved in disease pathogenesis through
CC EIF4E deregulation (PubMed:19556253).
CC -!- DISEASE: Note=A chromosomal aberration involving EIF4E has been
CC found in a patient with classic autism. Translocation
CC t(45)(q23q31.3). The breakpoint on chromosome 4 is located 56 kb
CC downstream of EIF4E (PubMed:19556253).
CC -!- SIMILARITY: Belongs to the eukaryotic initiation factor 4E family.
CC -!- CAUTION: Was originally thought to be phosphorylated on Ser-53
CC (PubMed:3112145); this was later shown to be wrong
CC (PubMed:7665584).
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/EIF4EID40431ch4q23.html";
CC -----------------------------------------------------------------------
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DR EMBL; M15353; AAC13647.1; -; mRNA.
DR EMBL; AK300982; BAH13387.1; -; mRNA.
DR EMBL; AC019131; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093836; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC012611; AAH12611.1; -; mRNA.
DR EMBL; BC035166; AAH35166.1; -; mRNA.
DR EMBL; BC043226; AAH43226.1; -; mRNA.
DR EMBL; BM849222; -; NOT_ANNOTATED_CDS; mRNA.
DR PIR; A26411; A26411.
DR RefSeq; NP_001124150.1; NM_001130678.1.
DR RefSeq; NP_001124151.1; NM_001130679.1.
DR RefSeq; NP_001959.1; NM_001968.3.
DR UniGene; Hs.249718; -.
DR PDB; 1IPB; X-ray; 2.00 A; A=1-217.
DR PDB; 1IPC; X-ray; 2.00 A; A=1-217.
DR PDB; 1WKW; X-ray; 2.10 A; A=27-217.
DR PDB; 2GPQ; NMR; -; A=1-217.
DR PDB; 2V8W; X-ray; 2.30 A; A/E=1-217.
DR PDB; 2V8X; X-ray; 2.30 A; A/E=1-217.
DR PDB; 2V8Y; X-ray; 2.10 A; A/E=1-217.
DR PDB; 2W97; X-ray; 2.29 A; A/B=1-217.
DR PDB; 3AM7; X-ray; 2.20 A; A=27-217.
DR PDB; 3TF2; X-ray; 2.10 A; A/B/C/D=1-217.
DR PDB; 3U7X; X-ray; 2.10 A; A/B=1-217.
DR PDB; 4AZA; X-ray; 2.16 A; A/C=1-217.
DR PDB; 4DT6; X-ray; 2.60 A; A=1-217.
DR PDB; 4DUM; X-ray; 2.95 A; A=1-217.
DR PDBsum; 1IPB; -.
DR PDBsum; 1IPC; -.
DR PDBsum; 1WKW; -.
DR PDBsum; 2GPQ; -.
DR PDBsum; 2V8W; -.
DR PDBsum; 2V8X; -.
DR PDBsum; 2V8Y; -.
DR PDBsum; 2W97; -.
DR PDBsum; 3AM7; -.
DR PDBsum; 3TF2; -.
DR PDBsum; 3U7X; -.
DR PDBsum; 4AZA; -.
DR PDBsum; 4DT6; -.
DR PDBsum; 4DUM; -.
DR ProteinModelPortal; P06730; -.
DR SMR; P06730; 1-217.
DR DIP; DIP-22N; -.
DR IntAct; P06730; 30.
DR MINT; MINT-85626; -.
DR STRING; 9606.ENSP00000280892; -.
DR BindingDB; P06730; -.
DR ChEMBL; CHEMBL4848; -.
DR PhosphoSite; P06730; -.
DR DMDM; 1352435; -.
DR OGP; P06730; -.
DR REPRODUCTION-2DPAGE; IPI00027485; -.
DR PaxDb; P06730; -.
DR PRIDE; P06730; -.
DR DNASU; 1977; -.
DR Ensembl; ENST00000280892; ENSP00000280892; ENSG00000151247.
DR Ensembl; ENST00000450253; ENSP00000389624; ENSG00000151247.
DR Ensembl; ENST00000505992; ENSP00000425561; ENSG00000151247.
DR GeneID; 1977; -.
DR KEGG; hsa:1977; -.
DR UCSC; uc003hue.2; human.
DR CTD; 1977; -.
DR GeneCards; GC04M099799; -.
DR H-InvDB; HIX0039231; -.
DR HGNC; HGNC:3287; EIF4E.
DR HPA; CAB004077; -.
DR HPA; CAB016316; -.
DR MIM; 133440; gene.
DR MIM; 615091; phenotype.
DR neXtProt; NX_P06730; -.
DR Orphanet; 106; Autism.
DR PharmGKB; PA27714; -.
DR eggNOG; COG5053; -.
DR HOGENOM; HOG000186751; -.
DR HOVERGEN; HBG006130; -.
DR KO; K03259; -.
DR OMA; NDENTAP; -.
DR OrthoDB; EOG7QRQVM; -.
DR PhylomeDB; P06730; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_1675; mRNA Processing.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P06730; -.
DR ChiTaRS; EIF4E; human.
DR EvolutionaryTrace; P06730; -.
DR GeneWiki; EIF4E; -.
DR GenomeRNAi; 1977; -.
DR NextBio; 7999; -.
DR PRO; PR:P06730; -.
DR ArrayExpress; P06730; -.
DR Bgee; P06730; -.
DR CleanEx; HS_EIF4E; -.
DR Genevestigator; P06730; -.
DR GO; GO:0033391; C:chromatoid body; IEA:Ensembl.
DR GO; GO:0000932; C:cytoplasmic mRNA processing body; IDA:MGI.
DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016281; C:eukaryotic translation initiation factor 4F complex; IDA:UniProtKB.
DR GO; GO:0005845; C:mRNA cap binding complex; IDA:UniProtKB.
DR GO; GO:0016442; C:RISC complex; IDA:MGI.
DR GO; GO:0000339; F:RNA cap binding; TAS:ProtInc.
DR GO; GO:0003743; F:translation initiation factor activity; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0006406; P:mRNA export from nucleus; TAS:Reactome.
DR GO; GO:0000289; P:nuclear-transcribed mRNA poly(A) tail shortening; TAS:Reactome.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0006417; P:regulation of translation; IDA:UniProtKB.
DR Gene3D; 3.30.760.10; -; 1.
DR InterPro; IPR023398; TIF_eIF4e-like_dom.
DR InterPro; IPR001040; TIF_eIF_4E.
DR InterPro; IPR019770; TIF_eIF_4E_CS.
DR PANTHER; PTHR11960; PTHR11960; 1.
DR Pfam; PF01652; IF4E; 1.
DR SUPFAM; SSF55418; SSF55418; 1.
DR PROSITE; PS00813; IF4E; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Chromosomal rearrangement; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Host-virus interaction; Initiation factor;
KW Phosphoprotein; Protein biosynthesis; Reference proteome; RNA-binding;
KW Translation regulation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 217 Eukaryotic translation initiation factor
FT 4E.
FT /FTId=PRO_0000193634.
FT REGION 37 40 EIF4EBP1/2/3 binding.
FT REGION 56 57 7-methylguanosine-containing mRNA cap
FT binding.
FT REGION 73 77 EIF4EBP1/2/3 binding.
FT REGION 102 103 7-methylguanosine-containing mRNA cap
FT binding.
FT REGION 132 139 EIF4EBP1/2/3 binding.
FT REGION 157 162 7-methylguanosine-containing mRNA cap
FT binding.
FT REGION 205 207 7-methylguanosine-containing mRNA cap
FT binding.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 209 209 Phosphoserine; by PKC and MKNK2.
FT VAR_SEQ 1 6 MATVEP -> MLDLTSRGQVGTSRRMAEAACSAHFL (in
FT isoform 3).
FT /FTId=VSP_043591.
FT VAR_SEQ 133 133 T -> TRWDLAMLPRLVSNFWPQVILPLQPPKVLELQ (in
FT isoform 2).
FT /FTId=VSP_042014.
FT MUTAGEN 53 53 S->A,D: No effect on phosphorylation
FT level nor incorporation into eIF4F
FT complex.
FT MUTAGEN 73 73 W->A: Abolishes binding to EIF4EBP1.
FT MUTAGEN 102 102 W->L: Decrease in mRNA cap binding; when
FT associated with A-105.
FT MUTAGEN 103 103 E->A: No effect.
FT MUTAGEN 104 104 D->A: No effect.
FT MUTAGEN 105 105 E->A: Decrease in mRNA cap binding; when
FT associated with L-102.
FT MUTAGEN 119 119 K->A: Higher affinity for EIF4G1.
FT CONFLICT 127 127 D -> N (in Ref. 5; AAH12611).
FT HELIX 31 33
FT STRAND 38 48
FT STRAND 52 54
FT HELIX 57 59
FT STRAND 60 68
FT HELIX 69 78
FT HELIX 82 84
FT STRAND 90 95
FT STRAND 100 103
FT TURN 105 109
FT STRAND 111 116
FT HELIX 121 124
FT HELIX 126 138
FT TURN 139 142
FT HELIX 143 148
FT STRAND 149 155
FT STRAND 162 168
FT HELIX 173 187
FT TURN 188 192
FT STRAND 196 199
FT HELIX 200 202
FT STRAND 206 208
FT STRAND 214 216
SQ SEQUENCE 217 AA; 25097 MW; B869B8DE615E699D CRC64;
MATVEPETTP TPNPPTTEEE KTESNQEVAN PEHYIKHPLQ NRWALWFFKN DKSKTWQANL
RLISKFDTVE DFWALYNHIQ LSSNLMPGCD YSLFKDGIEP MWEDEKNKRG GRWLITLNKQ
QRRSDLDRFW LETLLCLIGE SFDDYSDDVC GAVVNVRAKG DKIAIWTTEC ENREAVTHIG
RVYKERLGLP PKIVIGYQSH ADTATKSGST TKNRFVV
//
MIM
133440
*RECORD*
*FIELD* NO
133440
*FIELD* TI
*133440 EUKARYOTIC TRANSLATION INITIATION FACTOR 4E; EIF4E
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 4E FAMILY, MEMBER 1; EIF4E1;;
read moreEIF4E FAMILY, MEMBER 1;;
EIF4E-LIKE 1; EIF4EL1;;
MESSENGER RNA CAP-BINDING PROTEIN EIF4E
*FIELD* TX
DESCRIPTION
All eukaryotic cellular mRNAs are blocked at their 5-prime ends with the
7-methylguanosine cap structure, m7GpppX (where X is any nucleotide).
This structure is involved in several cellular processes including
enhanced translational efficiency, splicing, mRNA stability, and RNA
nuclear export. EIF4E is a eukaryotic translation initiation factor
involved in directing ribosomes to the cap structure of mRNAs. It is a
24-kD polypeptide that exists as both a free form and as part of a
multiprotein complex termed EIF4F. The EIF4E polypeptide is the
rate-limiting component of the eukaryotic translation apparatus and is
involved in the mRNA-ribosome binding step of eukaryotic protein
synthesis. The other subunits of EIF4F are a 50-kD polypeptide, termed
EIF4A (see 601102), that possesses ATPase and RNA helicase activities,
and a 220-kD polypeptide, EIF4G (600495) (summary by Rychlik et al.,
1987).
CLONING
Rychlik et al. (1987) cloned and sequenced EIF4E from human
erythrocytes.
GENE FUNCTION
Pause et al. (1994) identified 2 homologous proteins, EIF4EBP1 (602223)
and EIF4EBP2 (602224), that bind to EIF4E and may regulate its activity.
Jones et al. (1997) stated that EIF4E is the rate-limiting component in
protein synthesis and may play a role in growth regulation. The
overexpression of EIF4E can cause malignant transformation.
Waskiewicz et al. (1997) identified EIF4E as a potential physiologic
substrate for Mnk1 (MKNK1; 606724) and Mnk2 (MKNK2; 605069) in mouse.
Using coimmunoprecipitation experiments, Pyronnet et al. (1999)
demonstrated that MNK1 interacts with the EIF4F complex via its
interaction with the C-terminal region of EIF4G, not through a direct
interaction with EIF4E. An EIF4E mutant lacking EIF4G-binding capability
was poorly phosphorylated in cells. Pyronnet et al. (1999) hypothesized
that EIF4G provides a docking site for MNK1 to phosphorylate EIF4E.
In mammals, MTOR (601231) cooperates with PI3K (see 171834)-dependent
effectors in a biochemical signaling pathway to regulate the size of
proliferating cells. Fingar et al. (2002) presented evidence that rat
S6k1 alpha-II (608938), Eif4e, and Eif4ebp1 mediate Mtor-dependent cell
size control.
Using a murine lymphoma model, Wendel et al. (2004) demonstrated that
Akt (164730) promotes tumorigenesis and drug resistance by disrupting
apoptosis, and that disruption of Akt signaling using the mTOR inhibitor
rapamycin reverses chemoresistance in lymphomas expressing Akt, but not
in those with other apoptotic defects. The translational regulator
Eif4e, which acts downstream of Akt and mTOR, recapitulated the action
of Akt in tumorigenesis and drug resistance but was unable to confer
sensitivity to rapamycin and chemotherapy. Wendel et al. (2004)
concluded that their results established Akt signaling through mTOR and
Eif4e as an important mechanism of oncogenesis and drug resistance in
vivo and revealed how targeting apoptotic programs can restore drug
sensitivity in a genotype-dependent manner.
Syntichaki et. al. (2007) showed that loss of a specific eIF4E isoform,
Ife2, that functions in somatic tissues reduces global protein
synthesis, protects from oxidative stress, and extends life span in
Caenorhabditis elegans. Life span extension was independent of the
forkhead transcription factor Daf16 (see 136533), which mediates the
effects of the insulin-like signaling pathway on aging. Furthermore,
Ife2 deficiency further extended the life span of long-lived 'age' and
'daf' nematode mutants. Similarly, lack of Ife2 enhanced the long-lived
phenotype of 'clk' and dietary-restricted 'eat' mutant animals.
Knockdown of target of rapamycin (Tor; see 601231), a
phosphatidylinositol kinase-related kinase that controls protein
synthesis in response to nutrient cues, further increased the longevity
of Ife2 mutants. Thus, Syntichaki et al. (2007) concluded that signaling
via eIF4E in the soma influences aging in C. elegans.
BIOCHEMICAL FEATURES
Gross et al. (2003) reported the solution structure of the complex
between yeast Eif4e and the Eif4e-binding region of Eif4g (amino acids
393 to 490). Binding between these proteins triggered folding of the N
terminus of Eif4e with concomitant folding of Eif4g through a mutually
induced fit mechanism. Protein binding altered the conformation and/or
the stability of the cap binding slot, resulting in enhanced association
of Eif4e with the cap structure. Dissociation of the ternary complex was
slow, and the N terminus of Eif4e was required for these effects. Yeast
strains harboring mutants of Eif4e lacking key N-terminal residues
showed impaired growth, decreased polysome content, and reduced
interaction between Eif4e and Eif4g.
MAPPING
To map the human gene(s) for EIF4E, Pelletier et al. (1991) used
species-specific PCR DNA prepared from human/rodent somatic cell
hybrids. They showed that one of the human EIF4E genes (designated
EIF4EL1), probably the functional one, is located on 4p15-qter. A second
EIF4E gene, EIF4EL2, was located on human chromosome 20 by Southern blot
analysis of mapping panels established from human/rodent somatic cell
hybrids. The authors stated that this gene may represent a pseudogene.
As a critical component of the cap binding protein, EIF4E plays an
important role in growth regulation. There is evidence that it can
function as an oncogene. Jones et al. (1996) cloned genomic segments
from human DNA that encoded the promoter and first exon of human EIF4E.
Previous mapping studies localizing the EIF4E gene to chromosome 4 were
complicated by cross hybridization with multiple pseudogenes. On the
other hand, probes corresponding to the cloned promoter region of the
EIF4E gene detected unique bands in genomic Southern hybridizations.
Using oligonucleotide primers specific for the promoter region, Jones et
al. (1997) PCR-amplified the human gene in a chromosome 4-specific
human/rodent somatic cell panel. This panel mapped single-copy genomic
sequences for EIF4E in the region 4q21-q25.
Dorfman et al. (1991) determined that an EIF4E gene is located on mouse
chromosome 12. The gene mapped to mouse chromosome 12 is perhaps
unlikely to be the homolog of the gene that maps to human chromosome 4
in light of other information on the homologies of synteny between the 2
species. Jones et al. (1997) used PCR analysis of human-rodent somatic
cell panels to map the EIF4E gene to human chromosome 4q21-q25. They
noted that the mapping of this gene has been complicated by ambiguities
associated with pseudogenes; Jones et al. (1997) therefore used
sequences from the promoter region.
MOLECULAR GENETICS
Following the identification in a boy with classic autism (AUTS19;
615091) of a de novo balanced translocation in which one of the
breakpoints occurred within a proposed alternative transcript of EIF4E,
Neves-Pereira et al. (2009) screened 120 multiplex families with 2
autistic sibs for mutation in EIF4E. They identified an identical
single-base insertion in the promoter region (133440.0001) in 2
unrelated autistic sib pairs and in their respective fathers. The
variant was not found in 1,020 anonymous control samples.
Electrophoretic mobility shift assays and reporter gene studies showed
that this mutation enhances binding of a nuclear factor and EIF4E
promoter activity.
ANIMAL MODEL
Ruggero et al. (2004) generated transgenic mice that overexpressed Eif4e
and observed a marked increase in tumorigenesis in the mice when
compared with their wildtype littermates. When these transgenic mice
were intercrossed with a strain overexpressing the Myc oncogene (MYC;
190080), the double-transgenic offspring developed lymphoma at a
markedly accelerated rate. In double-transgenic B cells, the ability of
Myc to induce apoptosis was markedly reduced and Eif4e's induction of
cellular senescence in vivo in splenic B cells was completely abrogated.
Ruggero et al. (2004) suggested that activation of EIF4E may be a key
event in oncogenic transformation by phosphoinositide-3 kinase (see
171833) and Akt.
Gkogkas et al. (2013) demonstrated that knockout of the eukaryotic
translation initiation factor 4E-binding protein-2 (EIF4EBP2; 602224)
(an EIF4E repressor downstream of MTOR, 601231), or EIF4E overexpression
leads to increased translation of neuroligins, postsynaptic proteins
that are causally linked to autism spectrum disorders (ASDs). Mice with
knockout of Eif4ebp2 exhibit an increased ratio of excitatory to
inhibitory synaptic inputs and autistic-like behaviors (i.e., social
interaction deficits, altered communication, and repetitive/stereotyped
behaviors). Pharmacologic inhibition of Eif4e activity or normalization
of neuroligin-1 (600568), but not neuroligin-2 (606479), protein levels
restored the normal excitation/inhibition ratio and rectified the social
behavior deficits. Thus, Gkogkas et al. (2013) concluded that
translational control by EIF4E regulates the synthesis of neuroligins,
maintaining the excitation-to-inhibition balance, and its dysregulation
engenders ASD-like phenotypes.
Santini et al. (2013) found that genetically increasing the levels of
Eif4e in mice results in exaggerated cap-dependent translation and
aberrant behaviors reminiscent of autism, including repetitive and
perseverative behaviors and social interaction deficits. Moreover, these
autistic-like behaviors are accompanied by synaptic pathophysiology in
the medial prefrontal cortex, striatum, and hippocampus. The
autistic-like behaviors displayed by the Eif4e transgenic mice are
corrected by intracerebroventricular infusions of the cap-dependent
translation inhibitor 4EGI-1. Santini et al. (2013) concluded that their
findings demonstrated a causal relationship between exaggerated
cap-dependent translation, synaptic dysfunction, and aberrant behaviors
associated with autism.
*FIELD* AV
.0001
AUTISM, SUSCEPTIBILITY TO, 19
EIF4E, 1-BP INS, -25C
In 2 probands with autism (AUTS19; 615091) from unrelated families,
Neves-Pereira et al. (2009) detected the same single-basepair insertion
of a C nucleotide at position -25 in the promoter region of the EIF4E
gene. Each proband had an autistic sib, in whom the mutation was found;
the mutation was also found in the fathers of all 4 affected children,
but was not present in 2,040 control chromosomes. The insertion extended
a run of 7 C nucleotides to 8 within the EIF4E basal promoter element
(4EBE) that binds HNRNPK (600712). Neves-Pereira et al. (2009) performed
electrophoretic mobility shift assays and reporter gene studies and
showed that this mutation enhances binding of a nuclear factor, probably
HNRNPK, and EIF4E promoter activity. Neves-Pereira et al. (2009)
suggested that pharmacologic manipulation of EIF4E may provide
therapeutic benefit for those with autism caused by disturbance of the
converging pathways controlling EIF4E activity.
*FIELD* RF
1. Dorfman, J.; Lazaris-Karatzas, A.; Malo, D.; Sonenberg, N.; Gros,
P.: Chromosomal assignment of one of the mammalian translation initiation
factor eIF-4E genes. Genomics 9: 785-788, 1991.
2. Fingar, D. C.; Salama, S.; Tsou, C.; Harlow, E.; Blenis, J.: Mammalian
cell size is controlled by mTOR and its downstream targets S6K1 and
4EBP1/eIF4E. Genes Dev. 16: 1472-1487, 2002.
3. Gkogkas, C. G.; Khoutorsky A.; Ran, I.; Rampakakis, E.; Nevarko,
T.; Weatherill, D. B.; Vasuta, C.; Yee, S.; Truitt, M.; Dallaire,
P.; Major, F.; Lasko, P.; Ruggero, D.; Nader, K.; Lacaille, J.-C.;
Sonenberg, N.: Autism-related deficits via dysregulated eIF4E-dependent
translational control. Nature 493: 371-377, 2013.
4. Gross, J. D.; Moerke, N. J.; von der Haar, T.; Lugovskoy, A. A.;
Sachs, A. B.; McCarthy, J. E. G.; Wagner, G.: Ribosome loading onto
the mRNA cap is driven by conformational coupling between eIF4G and
eIF4E. Cell 115: 739-750, 2003.
5. Jones, R. M.; Branda, J.; Johnston, K. A.; Polymenis, M.; Gadd,
M.; Rustgi, A.; Callanan, L.; Schmidt, E. V.: An essential E box
in the promoter of the gene encoding the MRNA cap-binding protein
(eukaryotic initiation factor 4E) is a target for activation by c-myc. Molec.
Cell. Biol. 16: 4754-4764, 1996.
6. Jones, R. M.; MacDonald, M. E.; Branda, J.; Altherr, M. R.; Louis,
D. N.; Schmidt, E. V.: Assignment of the human gene encoding eukaryotic
initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4. Somat.
Cell Molec. Genet. 23: 221-223, 1997.
7. Neves-Pereira, M.; Muller, B.; Massie, D.; Williams, J. H. G.;
O'Brien, P. C. M.; Hughes, A.; Shen, S.-B.; St Clair, D.; Miedzybrodzka,
Z.: Deregulation of EIF4E: a novel mechanism for autism. (Letter) J.
Med. Genet. 46: 759-765, 2009. Note: Erratum: J. Med. Genet. 48:
421 only, 2011.
8. Pause, A.; Belsham, G. J.; Gingras, A.-C.; Donze, O.; Lin, T.-A.;
Lawrence, J. C., Jr.; Sonenberg, N.: Insulin-dependent stimulation
of protein synthesis by phosphorylation of a regulator of 5-prime-cap
function. Nature 371: 762-767, 1994.
9. Pelletier, J.; Brook, J. D.; Housman, D. E.: Assignment of two
of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes
to human chromosomes 4 and 20. Genomics 10: 1079-1082, 1991.
10. Pyronnet, S.; Imataka, H.; Gingras, A.-C.; Fukunaga, R.; Hunter,
T.; Sonenberg, N.: Human eukaryotic translation initiation factor
4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E. EMBO J. 18: 270-279,
1999.
11. Ruggero, D.; Montanaro, L.; Ma, L.; Xu, W.; Londei, P.; Cordon-Cardo,
C.; Pandolfi, P. P.: The translation factor eIF-4E promotes tumor
formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10:
484-486, 2004.
12. Rychlik, W.; Domier, L. L.; Gardner, P. R.; Hellmann, G. M.; Rhoads,
R. E.: Amino acid sequence of the mRNA cap-binding protein from human
tissues. Proc. Nat. Acad. Sci. 84: 945-949, 1987. Note: Erratum:
Proc. Nat. Acad. Sci. 89: 1148 only, 1992.
13. Santini, E.; Huynh, T. N.; MacAskill, A. F.; Carter, A. G.; Pierre,
P.; Ruggero, D.; Kaphzan, H.; Klann, E.: Exaggerated translation
causes synaptic and behavioural aberrations associated with autism. Nature 493:
411-415, 2013.
14. Syntichaki, P.; Troulinaki, K.; Tavernarakis, N.: eIF4E function
in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445:
922-926, 2007.
15. Waskiewicz, A. J.; Flynn, A.; Proud, C. G.; Cooper, J. A.: Mitogen-activated
protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO
J. 16: 1909-1920, 1997.
16. Wendel, H.-G.; de Stanchina, E.; Fridman, J. S.; Malina, A.; Ray,
S.; Kogan, S.; Cordon-Cardo, C.; Pelletier, J.; Lowe, S. W.: Survival
signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:
332-337, 2004.
*FIELD* CN
Ada Hamosh - updated: 2/20/2013
Nara Sobreira - updated: 3/10/2010
Ada Hamosh - updated: 4/22/2008
Patricia A. Hartz - updated: 6/2/2006
Patricia A. Hartz - updated: 9/23/2004
Marla J. F. O'Neill - updated: 5/5/2004
Ada Hamosh - updated: 4/7/2004
Dawn Watkins-Chow - updated: 2/27/2002
Victor A. McKusick - updated: 2/13/1998
Jennifer P. Macke - updated: 10/27/1997
*FIELD* CD
Victor A. McKusick: 7/3/1989
*FIELD* ED
alopez: 02/25/2013
alopez: 2/22/2013
terry: 2/20/2013
carol: 2/19/2013
carol: 12/11/2012
terry: 3/10/2010
carol: 8/27/2009
wwang: 2/20/2009
wwang: 10/6/2008
alopez: 5/14/2008
terry: 4/22/2008
mgross: 7/5/2006
mgross: 6/8/2006
terry: 6/2/2006
mgross: 2/17/2006
mgross: 9/23/2004
alopez: 5/28/2004
carol: 5/6/2004
carol: 5/5/2004
alopez: 4/8/2004
terry: 4/7/2004
mgross: 2/27/2002
alopez: 4/18/2001
dholmes: 3/9/1998
mark: 2/23/1998
terry: 2/13/1998
alopez: 1/16/1998
alopez: 1/6/1998
terry: 11/15/1996
terry: 11/18/1994
carol: 1/11/1993
carol: 1/6/1993
supermim: 3/16/1992
carol: 8/30/1991
carol: 8/12/1991
*RECORD*
*FIELD* NO
133440
*FIELD* TI
*133440 EUKARYOTIC TRANSLATION INITIATION FACTOR 4E; EIF4E
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 4E FAMILY, MEMBER 1; EIF4E1;;
read moreEIF4E FAMILY, MEMBER 1;;
EIF4E-LIKE 1; EIF4EL1;;
MESSENGER RNA CAP-BINDING PROTEIN EIF4E
*FIELD* TX
DESCRIPTION
All eukaryotic cellular mRNAs are blocked at their 5-prime ends with the
7-methylguanosine cap structure, m7GpppX (where X is any nucleotide).
This structure is involved in several cellular processes including
enhanced translational efficiency, splicing, mRNA stability, and RNA
nuclear export. EIF4E is a eukaryotic translation initiation factor
involved in directing ribosomes to the cap structure of mRNAs. It is a
24-kD polypeptide that exists as both a free form and as part of a
multiprotein complex termed EIF4F. The EIF4E polypeptide is the
rate-limiting component of the eukaryotic translation apparatus and is
involved in the mRNA-ribosome binding step of eukaryotic protein
synthesis. The other subunits of EIF4F are a 50-kD polypeptide, termed
EIF4A (see 601102), that possesses ATPase and RNA helicase activities,
and a 220-kD polypeptide, EIF4G (600495) (summary by Rychlik et al.,
1987).
CLONING
Rychlik et al. (1987) cloned and sequenced EIF4E from human
erythrocytes.
GENE FUNCTION
Pause et al. (1994) identified 2 homologous proteins, EIF4EBP1 (602223)
and EIF4EBP2 (602224), that bind to EIF4E and may regulate its activity.
Jones et al. (1997) stated that EIF4E is the rate-limiting component in
protein synthesis and may play a role in growth regulation. The
overexpression of EIF4E can cause malignant transformation.
Waskiewicz et al. (1997) identified EIF4E as a potential physiologic
substrate for Mnk1 (MKNK1; 606724) and Mnk2 (MKNK2; 605069) in mouse.
Using coimmunoprecipitation experiments, Pyronnet et al. (1999)
demonstrated that MNK1 interacts with the EIF4F complex via its
interaction with the C-terminal region of EIF4G, not through a direct
interaction with EIF4E. An EIF4E mutant lacking EIF4G-binding capability
was poorly phosphorylated in cells. Pyronnet et al. (1999) hypothesized
that EIF4G provides a docking site for MNK1 to phosphorylate EIF4E.
In mammals, MTOR (601231) cooperates with PI3K (see 171834)-dependent
effectors in a biochemical signaling pathway to regulate the size of
proliferating cells. Fingar et al. (2002) presented evidence that rat
S6k1 alpha-II (608938), Eif4e, and Eif4ebp1 mediate Mtor-dependent cell
size control.
Using a murine lymphoma model, Wendel et al. (2004) demonstrated that
Akt (164730) promotes tumorigenesis and drug resistance by disrupting
apoptosis, and that disruption of Akt signaling using the mTOR inhibitor
rapamycin reverses chemoresistance in lymphomas expressing Akt, but not
in those with other apoptotic defects. The translational regulator
Eif4e, which acts downstream of Akt and mTOR, recapitulated the action
of Akt in tumorigenesis and drug resistance but was unable to confer
sensitivity to rapamycin and chemotherapy. Wendel et al. (2004)
concluded that their results established Akt signaling through mTOR and
Eif4e as an important mechanism of oncogenesis and drug resistance in
vivo and revealed how targeting apoptotic programs can restore drug
sensitivity in a genotype-dependent manner.
Syntichaki et. al. (2007) showed that loss of a specific eIF4E isoform,
Ife2, that functions in somatic tissues reduces global protein
synthesis, protects from oxidative stress, and extends life span in
Caenorhabditis elegans. Life span extension was independent of the
forkhead transcription factor Daf16 (see 136533), which mediates the
effects of the insulin-like signaling pathway on aging. Furthermore,
Ife2 deficiency further extended the life span of long-lived 'age' and
'daf' nematode mutants. Similarly, lack of Ife2 enhanced the long-lived
phenotype of 'clk' and dietary-restricted 'eat' mutant animals.
Knockdown of target of rapamycin (Tor; see 601231), a
phosphatidylinositol kinase-related kinase that controls protein
synthesis in response to nutrient cues, further increased the longevity
of Ife2 mutants. Thus, Syntichaki et al. (2007) concluded that signaling
via eIF4E in the soma influences aging in C. elegans.
BIOCHEMICAL FEATURES
Gross et al. (2003) reported the solution structure of the complex
between yeast Eif4e and the Eif4e-binding region of Eif4g (amino acids
393 to 490). Binding between these proteins triggered folding of the N
terminus of Eif4e with concomitant folding of Eif4g through a mutually
induced fit mechanism. Protein binding altered the conformation and/or
the stability of the cap binding slot, resulting in enhanced association
of Eif4e with the cap structure. Dissociation of the ternary complex was
slow, and the N terminus of Eif4e was required for these effects. Yeast
strains harboring mutants of Eif4e lacking key N-terminal residues
showed impaired growth, decreased polysome content, and reduced
interaction between Eif4e and Eif4g.
MAPPING
To map the human gene(s) for EIF4E, Pelletier et al. (1991) used
species-specific PCR DNA prepared from human/rodent somatic cell
hybrids. They showed that one of the human EIF4E genes (designated
EIF4EL1), probably the functional one, is located on 4p15-qter. A second
EIF4E gene, EIF4EL2, was located on human chromosome 20 by Southern blot
analysis of mapping panels established from human/rodent somatic cell
hybrids. The authors stated that this gene may represent a pseudogene.
As a critical component of the cap binding protein, EIF4E plays an
important role in growth regulation. There is evidence that it can
function as an oncogene. Jones et al. (1996) cloned genomic segments
from human DNA that encoded the promoter and first exon of human EIF4E.
Previous mapping studies localizing the EIF4E gene to chromosome 4 were
complicated by cross hybridization with multiple pseudogenes. On the
other hand, probes corresponding to the cloned promoter region of the
EIF4E gene detected unique bands in genomic Southern hybridizations.
Using oligonucleotide primers specific for the promoter region, Jones et
al. (1997) PCR-amplified the human gene in a chromosome 4-specific
human/rodent somatic cell panel. This panel mapped single-copy genomic
sequences for EIF4E in the region 4q21-q25.
Dorfman et al. (1991) determined that an EIF4E gene is located on mouse
chromosome 12. The gene mapped to mouse chromosome 12 is perhaps
unlikely to be the homolog of the gene that maps to human chromosome 4
in light of other information on the homologies of synteny between the 2
species. Jones et al. (1997) used PCR analysis of human-rodent somatic
cell panels to map the EIF4E gene to human chromosome 4q21-q25. They
noted that the mapping of this gene has been complicated by ambiguities
associated with pseudogenes; Jones et al. (1997) therefore used
sequences from the promoter region.
MOLECULAR GENETICS
Following the identification in a boy with classic autism (AUTS19;
615091) of a de novo balanced translocation in which one of the
breakpoints occurred within a proposed alternative transcript of EIF4E,
Neves-Pereira et al. (2009) screened 120 multiplex families with 2
autistic sibs for mutation in EIF4E. They identified an identical
single-base insertion in the promoter region (133440.0001) in 2
unrelated autistic sib pairs and in their respective fathers. The
variant was not found in 1,020 anonymous control samples.
Electrophoretic mobility shift assays and reporter gene studies showed
that this mutation enhances binding of a nuclear factor and EIF4E
promoter activity.
ANIMAL MODEL
Ruggero et al. (2004) generated transgenic mice that overexpressed Eif4e
and observed a marked increase in tumorigenesis in the mice when
compared with their wildtype littermates. When these transgenic mice
were intercrossed with a strain overexpressing the Myc oncogene (MYC;
190080), the double-transgenic offspring developed lymphoma at a
markedly accelerated rate. In double-transgenic B cells, the ability of
Myc to induce apoptosis was markedly reduced and Eif4e's induction of
cellular senescence in vivo in splenic B cells was completely abrogated.
Ruggero et al. (2004) suggested that activation of EIF4E may be a key
event in oncogenic transformation by phosphoinositide-3 kinase (see
171833) and Akt.
Gkogkas et al. (2013) demonstrated that knockout of the eukaryotic
translation initiation factor 4E-binding protein-2 (EIF4EBP2; 602224)
(an EIF4E repressor downstream of MTOR, 601231), or EIF4E overexpression
leads to increased translation of neuroligins, postsynaptic proteins
that are causally linked to autism spectrum disorders (ASDs). Mice with
knockout of Eif4ebp2 exhibit an increased ratio of excitatory to
inhibitory synaptic inputs and autistic-like behaviors (i.e., social
interaction deficits, altered communication, and repetitive/stereotyped
behaviors). Pharmacologic inhibition of Eif4e activity or normalization
of neuroligin-1 (600568), but not neuroligin-2 (606479), protein levels
restored the normal excitation/inhibition ratio and rectified the social
behavior deficits. Thus, Gkogkas et al. (2013) concluded that
translational control by EIF4E regulates the synthesis of neuroligins,
maintaining the excitation-to-inhibition balance, and its dysregulation
engenders ASD-like phenotypes.
Santini et al. (2013) found that genetically increasing the levels of
Eif4e in mice results in exaggerated cap-dependent translation and
aberrant behaviors reminiscent of autism, including repetitive and
perseverative behaviors and social interaction deficits. Moreover, these
autistic-like behaviors are accompanied by synaptic pathophysiology in
the medial prefrontal cortex, striatum, and hippocampus. The
autistic-like behaviors displayed by the Eif4e transgenic mice are
corrected by intracerebroventricular infusions of the cap-dependent
translation inhibitor 4EGI-1. Santini et al. (2013) concluded that their
findings demonstrated a causal relationship between exaggerated
cap-dependent translation, synaptic dysfunction, and aberrant behaviors
associated with autism.
*FIELD* AV
.0001
AUTISM, SUSCEPTIBILITY TO, 19
EIF4E, 1-BP INS, -25C
In 2 probands with autism (AUTS19; 615091) from unrelated families,
Neves-Pereira et al. (2009) detected the same single-basepair insertion
of a C nucleotide at position -25 in the promoter region of the EIF4E
gene. Each proband had an autistic sib, in whom the mutation was found;
the mutation was also found in the fathers of all 4 affected children,
but was not present in 2,040 control chromosomes. The insertion extended
a run of 7 C nucleotides to 8 within the EIF4E basal promoter element
(4EBE) that binds HNRNPK (600712). Neves-Pereira et al. (2009) performed
electrophoretic mobility shift assays and reporter gene studies and
showed that this mutation enhances binding of a nuclear factor, probably
HNRNPK, and EIF4E promoter activity. Neves-Pereira et al. (2009)
suggested that pharmacologic manipulation of EIF4E may provide
therapeutic benefit for those with autism caused by disturbance of the
converging pathways controlling EIF4E activity.
*FIELD* RF
1. Dorfman, J.; Lazaris-Karatzas, A.; Malo, D.; Sonenberg, N.; Gros,
P.: Chromosomal assignment of one of the mammalian translation initiation
factor eIF-4E genes. Genomics 9: 785-788, 1991.
2. Fingar, D. C.; Salama, S.; Tsou, C.; Harlow, E.; Blenis, J.: Mammalian
cell size is controlled by mTOR and its downstream targets S6K1 and
4EBP1/eIF4E. Genes Dev. 16: 1472-1487, 2002.
3. Gkogkas, C. G.; Khoutorsky A.; Ran, I.; Rampakakis, E.; Nevarko,
T.; Weatherill, D. B.; Vasuta, C.; Yee, S.; Truitt, M.; Dallaire,
P.; Major, F.; Lasko, P.; Ruggero, D.; Nader, K.; Lacaille, J.-C.;
Sonenberg, N.: Autism-related deficits via dysregulated eIF4E-dependent
translational control. Nature 493: 371-377, 2013.
4. Gross, J. D.; Moerke, N. J.; von der Haar, T.; Lugovskoy, A. A.;
Sachs, A. B.; McCarthy, J. E. G.; Wagner, G.: Ribosome loading onto
the mRNA cap is driven by conformational coupling between eIF4G and
eIF4E. Cell 115: 739-750, 2003.
5. Jones, R. M.; Branda, J.; Johnston, K. A.; Polymenis, M.; Gadd,
M.; Rustgi, A.; Callanan, L.; Schmidt, E. V.: An essential E box
in the promoter of the gene encoding the MRNA cap-binding protein
(eukaryotic initiation factor 4E) is a target for activation by c-myc. Molec.
Cell. Biol. 16: 4754-4764, 1996.
6. Jones, R. M.; MacDonald, M. E.; Branda, J.; Altherr, M. R.; Louis,
D. N.; Schmidt, E. V.: Assignment of the human gene encoding eukaryotic
initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4. Somat.
Cell Molec. Genet. 23: 221-223, 1997.
7. Neves-Pereira, M.; Muller, B.; Massie, D.; Williams, J. H. G.;
O'Brien, P. C. M.; Hughes, A.; Shen, S.-B.; St Clair, D.; Miedzybrodzka,
Z.: Deregulation of EIF4E: a novel mechanism for autism. (Letter) J.
Med. Genet. 46: 759-765, 2009. Note: Erratum: J. Med. Genet. 48:
421 only, 2011.
8. Pause, A.; Belsham, G. J.; Gingras, A.-C.; Donze, O.; Lin, T.-A.;
Lawrence, J. C., Jr.; Sonenberg, N.: Insulin-dependent stimulation
of protein synthesis by phosphorylation of a regulator of 5-prime-cap
function. Nature 371: 762-767, 1994.
9. Pelletier, J.; Brook, J. D.; Housman, D. E.: Assignment of two
of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes
to human chromosomes 4 and 20. Genomics 10: 1079-1082, 1991.
10. Pyronnet, S.; Imataka, H.; Gingras, A.-C.; Fukunaga, R.; Hunter,
T.; Sonenberg, N.: Human eukaryotic translation initiation factor
4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E. EMBO J. 18: 270-279,
1999.
11. Ruggero, D.; Montanaro, L.; Ma, L.; Xu, W.; Londei, P.; Cordon-Cardo,
C.; Pandolfi, P. P.: The translation factor eIF-4E promotes tumor
formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10:
484-486, 2004.
12. Rychlik, W.; Domier, L. L.; Gardner, P. R.; Hellmann, G. M.; Rhoads,
R. E.: Amino acid sequence of the mRNA cap-binding protein from human
tissues. Proc. Nat. Acad. Sci. 84: 945-949, 1987. Note: Erratum:
Proc. Nat. Acad. Sci. 89: 1148 only, 1992.
13. Santini, E.; Huynh, T. N.; MacAskill, A. F.; Carter, A. G.; Pierre,
P.; Ruggero, D.; Kaphzan, H.; Klann, E.: Exaggerated translation
causes synaptic and behavioural aberrations associated with autism. Nature 493:
411-415, 2013.
14. Syntichaki, P.; Troulinaki, K.; Tavernarakis, N.: eIF4E function
in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445:
922-926, 2007.
15. Waskiewicz, A. J.; Flynn, A.; Proud, C. G.; Cooper, J. A.: Mitogen-activated
protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO
J. 16: 1909-1920, 1997.
16. Wendel, H.-G.; de Stanchina, E.; Fridman, J. S.; Malina, A.; Ray,
S.; Kogan, S.; Cordon-Cardo, C.; Pelletier, J.; Lowe, S. W.: Survival
signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:
332-337, 2004.
*FIELD* CN
Ada Hamosh - updated: 2/20/2013
Nara Sobreira - updated: 3/10/2010
Ada Hamosh - updated: 4/22/2008
Patricia A. Hartz - updated: 6/2/2006
Patricia A. Hartz - updated: 9/23/2004
Marla J. F. O'Neill - updated: 5/5/2004
Ada Hamosh - updated: 4/7/2004
Dawn Watkins-Chow - updated: 2/27/2002
Victor A. McKusick - updated: 2/13/1998
Jennifer P. Macke - updated: 10/27/1997
*FIELD* CD
Victor A. McKusick: 7/3/1989
*FIELD* ED
alopez: 02/25/2013
alopez: 2/22/2013
terry: 2/20/2013
carol: 2/19/2013
carol: 12/11/2012
terry: 3/10/2010
carol: 8/27/2009
wwang: 2/20/2009
wwang: 10/6/2008
alopez: 5/14/2008
terry: 4/22/2008
mgross: 7/5/2006
mgross: 6/8/2006
terry: 6/2/2006
mgross: 2/17/2006
mgross: 9/23/2004
alopez: 5/28/2004
carol: 5/6/2004
carol: 5/5/2004
alopez: 4/8/2004
terry: 4/7/2004
mgross: 2/27/2002
alopez: 4/18/2001
dholmes: 3/9/1998
mark: 2/23/1998
terry: 2/13/1998
alopez: 1/16/1998
alopez: 1/6/1998
terry: 11/15/1996
terry: 11/18/1994
carol: 1/11/1993
carol: 1/6/1993
supermim: 3/16/1992
carol: 8/30/1991
carol: 8/12/1991
MIM
615091
*RECORD*
*FIELD* NO
615091
*FIELD* TI
#615091 AUTISM, SUSCEPTIBILITY TO, 19; AUTS19
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morevariation in the EIF4E gene (133440) on chromosome 4q21-q25 influences
susceptibility to autism.
For a phenotypic description and a discussion of genetic heterogeneity
of autism, see 209850.
CYTOGENETICS
Neves-Pereira et al. (2009) identified a boy with classic autism and a
de novo balanced 46,XY,t(4;5)q23;q31.3) translocation. There was no
family history of autism and the child had no dysmorphic features other
than a double hair whorl on the crown. He demonstrated a typical and
severe autistic phenotype. The breakpoint on chromosome 4 maps 56 kb
downstream of EIF4E (133440), a region found to be associated with
autism (Yonan et al., 2003; Schellenberg et al., 2006).
MOLECULAR GENETICS
To investigate a role for the EIF4E gene in autism susceptibility,
Neves-Pereira et al. (2009) screened 120 multiplex families with 2
autistic sibs from the Autism Genetic Research Exchange (AGRE)
collection for mutations in the coding regions and promoter of EIF4E. In
2 independent families direct sequencing revealed a heterozygous
single-base insertion in the EIF4E promoter region (133440.0001) in the
proband. In both of the families the variant was present in the second
autistic sib and the father. The variant was not found in 1,020
anonymous control samples.
ANIMAL MODEL
Gkogkas et al. (2013) demonstrated that knockout of the eukaryotic
translation initiation factor 4E-binding protein-2 (EIF4EBP2; 602224)
(an EIF4E repressor downstream of MTOR, 601231) or Eif4e overexpression
leads to increased translation of neuroligins, which are postsynaptic
proteins that are causally linked to autism spectrum disorders (ASDs).
Mice with knockout of Eif4ebp2 exhibit an increased ratio of excitatory
to inhibitory synaptic inputs and autistic-like behaviors (i.e., social
interaction deficits, altered communication, and repetitive/stereotyped
behaviors). Pharmacologic inhibition of Eif4e activity or normalization
of neuroligin-1 (600568), but not neuroligin-2 (606479), protein levels
restored the normal excitation/inhibition ratio and rectified the social
behavior deficits. Thus, Gkogkas et al. (2013) concluded that
translational control by EIF4E regulates the synthesis of neuroligins,
maintaining the excitation-to-inhibition balance, and its dysregulation
engenders ASD-like phenotypes.
Santini et al. (2013) found that genetically increasing the levels of
Eif4e in mice results in exaggerated cap-dependent translation and
aberrant behaviors reminiscent of autism, including repetitive and
perseverative behaviors and social interaction deficits. Moreover, these
autistic-like behaviors are accompanied by synaptic pathophysiology in
the medial prefrontal cortex, striatum, and hippocampus. The
autistic-like behaviors displayed by the Eif4e transgenic mice are
corrected by intracerebroventricular infusions of the cap-dependent
translation inhibitor 4EGI-1. Santini et al. (2013) concluded that their
findings demonstrated a causal relationship between exaggerated
cap-dependent translation, synaptic dysfunction, and aberrant behaviors
associated with autism.
*FIELD* RF
1. Gkogkas, C. G.; Khoutorsky A.; Ran, I.; Rampakakis, E.; Nevarko,
T.; Weatherill, D. B.; Vasuta, C.; Yee, S.; Truitt, M.; Dallaire,
P.; Major, F.; Lasko, P.; Ruggero, D.; Nader, K.; Lacaille, J.-C.;
Sonenberg, N.: Autism-related deficits via dysregulated eIF4E-dependent
translational control. Nature 493: 371-377, 2013.
2. Neves-Pereira, M.; Muller, B.; Massie, D.; Williams, J. H. G.;
O'Brien, P. C. M.; Hughes, A.; Shen, S.-B.; St Clair, D.; Miedzybrodzka,
Z.: Deregulation of EIF4E: a novel mechanism for autism. J. Med.
Genet. 46: 759-765, 2009. Note: Erratum: J. Med. Genet. 48: 421
only, 2011.
3. Santini, E.; Huynh, T. N.; MacAskill, A. F.; Carter, A. G.; Pierre,
P.; Ruggero, D.; Kaphzan, H.; Klann, E.: Exaggerated translation
causes synaptic and behavioural aberrations associated with autism. Nature 493:
411-415, 2013.
4. Schellenberg, G. D.; Dawson, G.; Sung, Y. J.; Estes, A.; Munson,
J.; Rosenthal, E.; Rothstein, J.; Flodman, P.; Smith, M.; Coon, H.;
Leong, L.; Yu, C.-E.; Stodgell, C.; Rodier, P. M.; Spence, M. A.;
Minshew, N.; McMahon, W. M.; Wijsman, E. M.: Evidence for multiple
loci from a genome scan of autism kindreds. Molec. Psychiat. 11:
1049-1060, 2006.
5. Yonan, A. L.; Alarcon, M.; Cheng, R.; Magnusson, P. K. E.; Spence,
S. J.; Palmer, A. A.; Grunn, A.; Juo, S.-H. H.; Terwilliger, J. D.;
Liu, J.; Cantor, R. M.; Geschwind, D. H.; Gilliam, T. C.: A genomewide
screen of 345 families for autism-susceptibility loci. Am. J. Hum.
Genet. 73: 886-897, 2003.
*FIELD* CD
Ada Hamosh: 2/22/2013
*FIELD* ED
alopez: 02/25/2013
alopez: 2/22/2013
*RECORD*
*FIELD* NO
615091
*FIELD* TI
#615091 AUTISM, SUSCEPTIBILITY TO, 19; AUTS19
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morevariation in the EIF4E gene (133440) on chromosome 4q21-q25 influences
susceptibility to autism.
For a phenotypic description and a discussion of genetic heterogeneity
of autism, see 209850.
CYTOGENETICS
Neves-Pereira et al. (2009) identified a boy with classic autism and a
de novo balanced 46,XY,t(4;5)q23;q31.3) translocation. There was no
family history of autism and the child had no dysmorphic features other
than a double hair whorl on the crown. He demonstrated a typical and
severe autistic phenotype. The breakpoint on chromosome 4 maps 56 kb
downstream of EIF4E (133440), a region found to be associated with
autism (Yonan et al., 2003; Schellenberg et al., 2006).
MOLECULAR GENETICS
To investigate a role for the EIF4E gene in autism susceptibility,
Neves-Pereira et al. (2009) screened 120 multiplex families with 2
autistic sibs from the Autism Genetic Research Exchange (AGRE)
collection for mutations in the coding regions and promoter of EIF4E. In
2 independent families direct sequencing revealed a heterozygous
single-base insertion in the EIF4E promoter region (133440.0001) in the
proband. In both of the families the variant was present in the second
autistic sib and the father. The variant was not found in 1,020
anonymous control samples.
ANIMAL MODEL
Gkogkas et al. (2013) demonstrated that knockout of the eukaryotic
translation initiation factor 4E-binding protein-2 (EIF4EBP2; 602224)
(an EIF4E repressor downstream of MTOR, 601231) or Eif4e overexpression
leads to increased translation of neuroligins, which are postsynaptic
proteins that are causally linked to autism spectrum disorders (ASDs).
Mice with knockout of Eif4ebp2 exhibit an increased ratio of excitatory
to inhibitory synaptic inputs and autistic-like behaviors (i.e., social
interaction deficits, altered communication, and repetitive/stereotyped
behaviors). Pharmacologic inhibition of Eif4e activity or normalization
of neuroligin-1 (600568), but not neuroligin-2 (606479), protein levels
restored the normal excitation/inhibition ratio and rectified the social
behavior deficits. Thus, Gkogkas et al. (2013) concluded that
translational control by EIF4E regulates the synthesis of neuroligins,
maintaining the excitation-to-inhibition balance, and its dysregulation
engenders ASD-like phenotypes.
Santini et al. (2013) found that genetically increasing the levels of
Eif4e in mice results in exaggerated cap-dependent translation and
aberrant behaviors reminiscent of autism, including repetitive and
perseverative behaviors and social interaction deficits. Moreover, these
autistic-like behaviors are accompanied by synaptic pathophysiology in
the medial prefrontal cortex, striatum, and hippocampus. The
autistic-like behaviors displayed by the Eif4e transgenic mice are
corrected by intracerebroventricular infusions of the cap-dependent
translation inhibitor 4EGI-1. Santini et al. (2013) concluded that their
findings demonstrated a causal relationship between exaggerated
cap-dependent translation, synaptic dysfunction, and aberrant behaviors
associated with autism.
*FIELD* RF
1. Gkogkas, C. G.; Khoutorsky A.; Ran, I.; Rampakakis, E.; Nevarko,
T.; Weatherill, D. B.; Vasuta, C.; Yee, S.; Truitt, M.; Dallaire,
P.; Major, F.; Lasko, P.; Ruggero, D.; Nader, K.; Lacaille, J.-C.;
Sonenberg, N.: Autism-related deficits via dysregulated eIF4E-dependent
translational control. Nature 493: 371-377, 2013.
2. Neves-Pereira, M.; Muller, B.; Massie, D.; Williams, J. H. G.;
O'Brien, P. C. M.; Hughes, A.; Shen, S.-B.; St Clair, D.; Miedzybrodzka,
Z.: Deregulation of EIF4E: a novel mechanism for autism. J. Med.
Genet. 46: 759-765, 2009. Note: Erratum: J. Med. Genet. 48: 421
only, 2011.
3. Santini, E.; Huynh, T. N.; MacAskill, A. F.; Carter, A. G.; Pierre,
P.; Ruggero, D.; Kaphzan, H.; Klann, E.: Exaggerated translation
causes synaptic and behavioural aberrations associated with autism. Nature 493:
411-415, 2013.
4. Schellenberg, G. D.; Dawson, G.; Sung, Y. J.; Estes, A.; Munson,
J.; Rosenthal, E.; Rothstein, J.; Flodman, P.; Smith, M.; Coon, H.;
Leong, L.; Yu, C.-E.; Stodgell, C.; Rodier, P. M.; Spence, M. A.;
Minshew, N.; McMahon, W. M.; Wijsman, E. M.: Evidence for multiple
loci from a genome scan of autism kindreds. Molec. Psychiat. 11:
1049-1060, 2006.
5. Yonan, A. L.; Alarcon, M.; Cheng, R.; Magnusson, P. K. E.; Spence,
S. J.; Palmer, A. A.; Grunn, A.; Juo, S.-H. H.; Terwilliger, J. D.;
Liu, J.; Cantor, R. M.; Geschwind, D. H.; Gilliam, T. C.: A genomewide
screen of 345 families for autism-susceptibility loci. Am. J. Hum.
Genet. 73: 886-897, 2003.
*FIELD* CD
Ada Hamosh: 2/22/2013
*FIELD* ED
alopez: 02/25/2013
alopez: 2/22/2013