Full text data of YWHAE
YWHAE
[Confidence: high (present in two of the MS resources)]
14-3-3 protein epsilon; 14-3-3E
Note: presumably soluble (membrane word is not in UniProt keywords or features)
14-3-3 protein epsilon; 14-3-3E
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00000816
IPI00000816 14-3-3 protein epsilon 14-3-3 protein epsilon membrane n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a 2 1 1 cytoplasmic n/a expected molecular weight found in band > 188 kDa together with ubiquitin
IPI00000816 14-3-3 protein epsilon 14-3-3 protein epsilon membrane n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a 2 1 1 cytoplasmic n/a expected molecular weight found in band > 188 kDa together with ubiquitin
UniProt
P62258
ID 1433E_HUMAN Reviewed; 255 AA.
AC P62258; B3KY71; D3DTH5; P29360; P42655; Q4VJB6; Q53XZ5; Q63631;
read moreAC Q7M4R4;
DT 05-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=14-3-3 protein epsilon;
DE Short=14-3-3E;
GN Name=YWHAE;
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).
RX PubMed=7644510; DOI=10.1073/pnas.92.17.7892;
RA Conklin D.S., Galaktionov K., Beach D.;
RT "14-3-3 proteins associate with cdc25 phosphatases.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7892-7896(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8858348;
RA Chong S.S., Tanigami A., Roschke A.V., Ledbetter D.H.;
RT "14-3-3 epsilon has no homology to LIS1 and lies telomeric to it on
RT chromosome 17p13.3 outside the Miller-Dieker syndrome chromosome
RT region.";
RL Genome Res. 6:735-741(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8684458; DOI=10.1038/382308a0;
RA Jin D.-Y., Lyu M.S., Kozak C.A., Jeang K.-T.;
RT "Function of 14-3-3 proteins.";
RL Nature 382:308-308(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SV), AND ALTERNATIVE SPLICING.
RC TISSUE=Brain;
RX PubMed=20417184; DOI=10.1016/j.bbrc.2010.04.104;
RA Han D., Ye G., Liu T., Chen C., Yang X., Wan B., Pan Y., Yu L.;
RT "Functional identification of a novel 14-3-3 epsilon splicing variant
RT suggests dimerization is not necessary for 14-3-3 epsilon to inhibit
RT UV-induced apoptosis.";
RL Biochem. Biophys. Res. Commun. 396:401-406(2010).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RA Luk S.C.W., Lee C.Y., Waye M.M.Y.;
RT "Sequence determination of human epsilon 14-3-3 protein.";
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Tanigami A., Chong S.S., Ledbetter D.H.;
RT "14-3-3 epsilon genomic sequence.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND SV).
RC TISSUE=Caudate nucleus, Heart, and Subthalamic nucleus;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [11]
RP PROTEIN SEQUENCE OF 1-19.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [12]
RP PROTEIN SEQUENCE OF 1-19; 30-50 AND 131-170, ACETYLATION AT MET-1, AND
RP MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (MAY-2005) to UniProtKB.
RN [13]
RP PROTEIN SEQUENCE OF 103-108; 120-123; 131-141 AND 143-153.
RC TISSUE=Histiocytic lymphoma;
RX PubMed=2026444;
RA Demeter J., Medzihradszky D., Kha H., Goetzl E.J., Turck C.W.;
RT "Isolation and partial characterization of the structures of
RT fibroblast activating factor-related proteins from U937 cells.";
RL Immunology 72:350-354(1991).
RN [14]
RP PROTEIN SEQUENCE OF 131-141 AND 154-190, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (MAR-2007) to UniProtKB.
RN [15]
RP INTERACTION WITH HCV CORE PROTEIN.
RX PubMed=10644344; DOI=10.1128/JVI.74.4.1736-1741.2000;
RA Aoki H., Hayashi J., Moriyama M., Arakawa Y., Hino O.;
RT "Hepatitis C virus core protein interacts with 14-3-3 protein and
RT activates the kinase Raf-1.";
RL J. Virol. 74:1736-1741(2000).
RN [16]
RP INTERACTION WITH AANAT.
RX PubMed=11427721; DOI=10.1073/pnas.141118798;
RA Ganguly S., Gastel J.A., Weller J.L., Schwartz C., Jaffe H.,
RA Namboodiri M.A., Coon S.L., Hickman A.B., Rollag M., Obsil T.,
RA Beauverger P., Ferry G., Boutin J.A., Klein D.C.;
RT "Role of a pineal cAMP-operated arylalkylamine N-acetyltransferase/14-
RT 3-3-binding switch in melatonin synthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:8083-8088(2001).
RN [17]
RP INTERACTION WITH CDKN1B, AND SUBCELLULAR LOCATION.
RX PubMed=12042314; DOI=10.1074/jbc.M203668200;
RA Fujita N., Sato S., Katayama K., Tsuruo T.;
RT "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3
RT and cytoplasmic localization.";
RL J. Biol. Chem. 277:28706-28713(2002).
RN [18]
RP INTERACTION WITH GRB10.
RX PubMed=15722337; DOI=10.1074/jbc.M501477200;
RA Urschel S., Bassermann F., Bai R.Y., Munch S., Peschel C., Duyster J.;
RT "Phosphorylation of grb10 regulates its interaction with 14-3-3.";
RL J. Biol. Chem. 280:16987-16993(2005).
RN [19]
RP INTERACTION WITH ABL1, AND MASS SPECTROMETRY.
RX PubMed=15696159; DOI=10.1038/ncb1228;
RA Yoshida K., Yamaguchi T., Natsume T., Kufe D., Miki Y.;
RT "JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of
RT c-Abl in the apoptotic response to DNA damage.";
RL Nat. Cell Biol. 7:278-285(2005).
RN [20]
RP INTERACTION WITH YWHAZ.
RX PubMed=16376338; DOI=10.1016/j.febslet.2005.12.024;
RA Gu Y.-M., Jin Y.-H., Choi J.-K., Baek K.-H., Yeo C.-Y., Lee K.-Y.;
RT "Protein kinase A phosphorylates and regulates dimerization of 14-3-3
RT epsilon.";
RL FEBS Lett. 580:305-310(2006).
RN [21]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [22]
RP INTERACTION WITH GAB2.
RX PubMed=19172738; DOI=10.1038/emboj.2008.159;
RA Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P.,
RA Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D.,
RA Guilhaus M., James D.E., Daly R.J.;
RT "Phosphorylation-dependent binding of 14-3-3 terminates signalling by
RT the Gab2 docking protein.";
RL EMBO J. 27:2305-2316(2008).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [24]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [25]
RP INTERACTION WITH SRPK2.
RX PubMed=19592491; DOI=10.1074/jbc.M109.026237;
RA Jang S.W., Liu X., Fu H., Rees H., Yepes M., Levey A., Ye K.;
RT "Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell
RT cycle and cell death in neurons.";
RL J. Biol. Chem. 284:24512-24525(2009).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-50; LYS-69; LYS-118 AND
RP LYS-123, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-210, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [28]
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 [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-210, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1-233, MASS SPECTROMETRY,
RP INTERACTION WITH PHOSPHOSERINE MOTIFS, AND SUBUNIT.
RX PubMed=17085597; DOI=10.1073/pnas.0605779103;
RA Yang X., Lee W.H., Sobott F., Papagrigoriou E., Robinson C.V.,
RA Grossmann J.G., Sundstroem M., Doyle D.A., Elkins J.M.;
RT "Structural basis for protein-protein interactions in the 14-3-3
RT protein family.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:17237-17242(2006).
CC -!- FUNCTION: Adapter protein implicated in the regulation of a large
CC spectrum of both general and specialized signaling pathways. Binds
CC to a large number of partners, usually by recognition of a
CC phosphoserine or phosphothreonine motif. Binding generally results
CC in the modulation of the activity of the binding partner.
CC -!- SUBUNIT: Homodimer. Heterodimerizes with YWHAZ. Interacts with
CC NDEL1, ARHGEF28 and TIAM2 (By similarity). Interacts with HCV core
CC protein. Interacts with ABL1 (phosphorylated form); the
CC interaction retains it in the cytoplasm. Weakly interacts with
CC CDKN1B. Interacts with GAB2. Interacts with phosphorylated GRB10.
CC Interacts with PKA-phosphorylated AANAT. Interacts with the
CC phosphorylated (by AKT1) form of SRPK2.
CC -!- INTERACTION:
CC O14727:APAF1; NbExp=2; IntAct=EBI-356498, EBI-446492;
CC O00257-3:CBX4; NbExp=2; IntAct=EBI-356498, EBI-4392727;
CC O94921:CDK14; NbExp=3; IntAct=EBI-356498, EBI-1043945;
CC Q9UKT5:FBXO4; NbExp=5; IntAct=EBI-356498, EBI-960409;
CC P56524:HDAC4; NbExp=4; IntAct=EBI-356498, EBI-308629;
CC Q14678-2:KANK1; NbExp=3; IntAct=EBI-356498, EBI-6173812;
CC Q5S007:LRRK2; NbExp=4; IntAct=EBI-356498, EBI-5323863;
CC O15151:MDM4; NbExp=3; IntAct=EBI-356498, EBI-398437;
CC P58340:MLF1; NbExp=3; IntAct=EBI-356498, EBI-721328;
CC O35244:Prdx6 (xeno); NbExp=2; IntAct=EBI-356498, EBI-915490;
CC P61588:Rnd3 (xeno); NbExp=2; IntAct=EBI-356498, EBI-6930266;
CC Q99469:STAC; NbExp=2; IntAct=EBI-356498, EBI-2652799;
CC Q9GZV5:WWTR1; NbExp=3; IntAct=EBI-356498, EBI-747743;
CC P31946:YWHAB; NbExp=3; IntAct=EBI-356498, EBI-359815;
CC P61981:YWHAG; NbExp=4; IntAct=EBI-356498, EBI-359832;
CC P63104:YWHAZ; NbExp=5; IntAct=EBI-356498, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Melanosome.
CC Note=Identified by mass spectrometry in melanosome fractions from
CC stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P62258-1; Sequence=Displayed;
CC Name=SV;
CC IsoId=P62258-2; Sequence=VSP_040621;
CC Note=Unable to dimerize with YWHAZ;
CC -!- SIMILARITY: Belongs to the 14-3-3 family.
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DR EMBL; U20972; AAC50175.1; -; mRNA.
DR EMBL; U54778; AAC50710.1; -; mRNA.
DR EMBL; U43399; AAC50625.1; -; mRNA.
DR EMBL; U43430; AAD00026.1; -; mRNA.
DR EMBL; U28936; AAA75301.1; -; mRNA.
DR EMBL; AB017103; BAA32538.1; -; Genomic_DNA.
DR EMBL; AY883089; AAX68683.1; -; mRNA.
DR EMBL; AK128785; BAG54733.1; -; mRNA.
DR EMBL; AK295260; BAG58249.1; -; mRNA.
DR EMBL; AK316185; BAH14556.1; -; mRNA.
DR EMBL; BT007161; AAP35825.1; -; mRNA.
DR EMBL; CH471108; EAW90628.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90629.1; -; Genomic_DNA.
DR EMBL; BC000179; AAH00179.1; -; mRNA.
DR EMBL; BC001440; AAH01440.1; -; mRNA.
DR PIR; A61235; A61235.
DR PIR; I38947; I38947.
DR RefSeq; NP_006752.1; NM_006761.4.
DR UniGene; Hs.513851; -.
DR PDB; 2BR9; X-ray; 1.75 A; A=1-233.
DR PDB; 3UAL; X-ray; 1.80 A; A=1-232.
DR PDB; 3UBW; X-ray; 1.90 A; A=1-234.
DR PDBsum; 2BR9; -.
DR PDBsum; 3UAL; -.
DR PDBsum; 3UBW; -.
DR ProteinModelPortal; P62258; -.
DR SMR; P62258; 3-232.
DR DIP; DIP-36676N; -.
DR IntAct; P62258; 146.
DR MINT; MINT-4998623; -.
DR STRING; 9606.ENSP00000264335; -.
DR PhosphoSite; P62258; -.
DR DMDM; 51702210; -.
DR OGP; P42655; -.
DR UCD-2DPAGE; P62258; -.
DR PaxDb; P62258; -.
DR PeptideAtlas; P62258; -.
DR PRIDE; P62258; -.
DR DNASU; 7531; -.
DR Ensembl; ENST00000264335; ENSP00000264335; ENSG00000108953.
DR Ensembl; ENST00000571732; ENSP00000461762; ENSG00000108953.
DR GeneID; 7531; -.
DR KEGG; hsa:7531; -.
DR UCSC; uc002fsj.3; human.
DR CTD; 7531; -.
DR GeneCards; GC17M001148; -.
DR H-InvDB; HIX0013751; -.
DR H-InvDB; HIX0030006; -.
DR HGNC; HGNC:12851; YWHAE.
DR HPA; CAB016200; -.
DR HPA; CAB021109; -.
DR HPA; CAB047350; -.
DR HPA; HPA008445; -.
DR MIM; 605066; gene.
DR neXtProt; NX_P62258; -.
DR Orphanet; 217385; 17p13.3 microduplication syndrome.
DR Orphanet; 261257; Distal 17p13.3 microdeletion syndrome.
DR Orphanet; 531; Miller-Dieker syndrome.
DR PharmGKB; PA37440; -.
DR eggNOG; COG5040; -.
DR HOVERGEN; HBG050423; -.
DR InParanoid; P62258; -.
DR KO; K06630; -.
DR OMA; MQESDKP; -.
DR OrthoDB; EOG7HHWT3; -.
DR PhylomeDB; P62258; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; P62258; -.
DR ChiTaRS; YWHAE; human.
DR EvolutionaryTrace; P62258; -.
DR GeneWiki; YWHAE; -.
DR GenomeRNAi; 7531; -.
DR NextBio; 29461; -.
DR PMAP-CutDB; P62258; -.
DR PRO; PR:P62258; -.
DR ArrayExpress; P62258; -.
DR Bgee; P62258; -.
DR CleanEx; HS_YWHAE; -.
DR Genevestigator; P62258; -.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005871; C:kinesin complex; IEA:Ensembl.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0015459; F:potassium channel regulator activity; IDA:BHF-UCL.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0035329; P:hippo signaling cascade; TAS:Reactome.
DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0086013; P:membrane repolarization involved in regulation of cardiac muscle cell action potential; IC:BHF-UCL.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:1902309; P:negative regulation of peptidyl-serine dephosphorylation; IDA:BHF-UCL.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:1900740; P:positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0006605; P:protein targeting; IEA:Ensembl.
DR GO; GO:0043281; P:regulation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IC:BHF-UCL.
DR GO; GO:0003064; P:regulation of heart rate by hormone; NAS:BHF-UCL.
DR GO; GO:0060306; P:regulation of membrane repolarization; IDA:BHF-UCL.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL.
DR Gene3D; 1.20.190.20; -; 1.
DR InterPro; IPR000308; 14-3-3.
DR InterPro; IPR023409; 14-3-3_CS.
DR InterPro; IPR023410; 14-3-3_domain.
DR PANTHER; PTHR18860; PTHR18860; 1.
DR Pfam; PF00244; 14-3-3; 1.
DR PIRSF; PIRSF000868; 14-3-3; 1.
DR PRINTS; PR00305; 1433ZETA.
DR SMART; SM00101; 14_3_3; 1.
DR SUPFAM; SSF48445; SSF48445; 1.
DR PROSITE; PS00796; 1433_1; 1.
DR PROSITE; PS00797; 1433_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Host-virus interaction;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1 255 14-3-3 protein epsilon.
FT /FTId=PRO_0000058618.
FT SITE 57 57 Interaction with phosphoserine on
FT interacting protein.
FT SITE 130 130 Interaction with phosphoserine on
FT interacting protein.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 50 50 N6-acetyllysine.
FT MOD_RES 69 69 N6-acetyllysine.
FT MOD_RES 118 118 N6-acetyllysine.
FT MOD_RES 123 123 N6-acetyllysine.
FT MOD_RES 210 210 Phosphoserine.
FT VAR_SEQ 1 22 Missing (in isoform SV).
FT /FTId=VSP_040621.
FT CONFLICT 106 107 KH -> NY (in Ref. 13; AA sequence).
FT CONFLICT 143 143 E -> F (in Ref. 13; AA sequence).
FT CONFLICT 148 148 S -> T (in Ref. 13; AA sequence).
FT HELIX 4 17
FT HELIX 20 31
FT HELIX 39 73
FT HELIX 76 106
FT HELIX 108 111
FT HELIX 115 135
FT HELIX 138 162
FT HELIX 168 183
FT HELIX 188 204
FT HELIX 205 208
FT TURN 211 213
FT HELIX 214 231
SQ SEQUENCE 255 AA; 29174 MW; 07817CCBD1F75B26 CRC64;
MDDREDLVYQ AKLAEQAERY DEMVESMKKV AGMDVELTVE ERNLLSVAYK NVIGARRASW
RIISSIEQKE ENKGGEDKLK MIREYRQMVE TELKLICCDI LDVLDKHLIP AANTGESKVF
YYKMKGDYHR YLAEFATGND RKEAAENSLV AYKAASDIAM TELPPTHPIR LGLALNFSVF
YYEILNSPDR ACRLAKAAFD DAIAELDTLS EESYKDSTLI MQLLRDNLTL WTSDMQGDGE
EQNKEALQDV EDENQ
//
ID 1433E_HUMAN Reviewed; 255 AA.
AC P62258; B3KY71; D3DTH5; P29360; P42655; Q4VJB6; Q53XZ5; Q63631;
read moreAC Q7M4R4;
DT 05-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=14-3-3 protein epsilon;
DE Short=14-3-3E;
GN Name=YWHAE;
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).
RX PubMed=7644510; DOI=10.1073/pnas.92.17.7892;
RA Conklin D.S., Galaktionov K., Beach D.;
RT "14-3-3 proteins associate with cdc25 phosphatases.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7892-7896(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8858348;
RA Chong S.S., Tanigami A., Roschke A.V., Ledbetter D.H.;
RT "14-3-3 epsilon has no homology to LIS1 and lies telomeric to it on
RT chromosome 17p13.3 outside the Miller-Dieker syndrome chromosome
RT region.";
RL Genome Res. 6:735-741(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8684458; DOI=10.1038/382308a0;
RA Jin D.-Y., Lyu M.S., Kozak C.A., Jeang K.-T.;
RT "Function of 14-3-3 proteins.";
RL Nature 382:308-308(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SV), AND ALTERNATIVE SPLICING.
RC TISSUE=Brain;
RX PubMed=20417184; DOI=10.1016/j.bbrc.2010.04.104;
RA Han D., Ye G., Liu T., Chen C., Yang X., Wan B., Pan Y., Yu L.;
RT "Functional identification of a novel 14-3-3 epsilon splicing variant
RT suggests dimerization is not necessary for 14-3-3 epsilon to inhibit
RT UV-induced apoptosis.";
RL Biochem. Biophys. Res. Commun. 396:401-406(2010).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RA Luk S.C.W., Lee C.Y., Waye M.M.Y.;
RT "Sequence determination of human epsilon 14-3-3 protein.";
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Tanigami A., Chong S.S., Ledbetter D.H.;
RT "14-3-3 epsilon genomic sequence.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND SV).
RC TISSUE=Caudate nucleus, Heart, and Subthalamic nucleus;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [11]
RP PROTEIN SEQUENCE OF 1-19.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [12]
RP PROTEIN SEQUENCE OF 1-19; 30-50 AND 131-170, ACETYLATION AT MET-1, AND
RP MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (MAY-2005) to UniProtKB.
RN [13]
RP PROTEIN SEQUENCE OF 103-108; 120-123; 131-141 AND 143-153.
RC TISSUE=Histiocytic lymphoma;
RX PubMed=2026444;
RA Demeter J., Medzihradszky D., Kha H., Goetzl E.J., Turck C.W.;
RT "Isolation and partial characterization of the structures of
RT fibroblast activating factor-related proteins from U937 cells.";
RL Immunology 72:350-354(1991).
RN [14]
RP PROTEIN SEQUENCE OF 131-141 AND 154-190, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (MAR-2007) to UniProtKB.
RN [15]
RP INTERACTION WITH HCV CORE PROTEIN.
RX PubMed=10644344; DOI=10.1128/JVI.74.4.1736-1741.2000;
RA Aoki H., Hayashi J., Moriyama M., Arakawa Y., Hino O.;
RT "Hepatitis C virus core protein interacts with 14-3-3 protein and
RT activates the kinase Raf-1.";
RL J. Virol. 74:1736-1741(2000).
RN [16]
RP INTERACTION WITH AANAT.
RX PubMed=11427721; DOI=10.1073/pnas.141118798;
RA Ganguly S., Gastel J.A., Weller J.L., Schwartz C., Jaffe H.,
RA Namboodiri M.A., Coon S.L., Hickman A.B., Rollag M., Obsil T.,
RA Beauverger P., Ferry G., Boutin J.A., Klein D.C.;
RT "Role of a pineal cAMP-operated arylalkylamine N-acetyltransferase/14-
RT 3-3-binding switch in melatonin synthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:8083-8088(2001).
RN [17]
RP INTERACTION WITH CDKN1B, AND SUBCELLULAR LOCATION.
RX PubMed=12042314; DOI=10.1074/jbc.M203668200;
RA Fujita N., Sato S., Katayama K., Tsuruo T.;
RT "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3
RT and cytoplasmic localization.";
RL J. Biol. Chem. 277:28706-28713(2002).
RN [18]
RP INTERACTION WITH GRB10.
RX PubMed=15722337; DOI=10.1074/jbc.M501477200;
RA Urschel S., Bassermann F., Bai R.Y., Munch S., Peschel C., Duyster J.;
RT "Phosphorylation of grb10 regulates its interaction with 14-3-3.";
RL J. Biol. Chem. 280:16987-16993(2005).
RN [19]
RP INTERACTION WITH ABL1, AND MASS SPECTROMETRY.
RX PubMed=15696159; DOI=10.1038/ncb1228;
RA Yoshida K., Yamaguchi T., Natsume T., Kufe D., Miki Y.;
RT "JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of
RT c-Abl in the apoptotic response to DNA damage.";
RL Nat. Cell Biol. 7:278-285(2005).
RN [20]
RP INTERACTION WITH YWHAZ.
RX PubMed=16376338; DOI=10.1016/j.febslet.2005.12.024;
RA Gu Y.-M., Jin Y.-H., Choi J.-K., Baek K.-H., Yeo C.-Y., Lee K.-Y.;
RT "Protein kinase A phosphorylates and regulates dimerization of 14-3-3
RT epsilon.";
RL FEBS Lett. 580:305-310(2006).
RN [21]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [22]
RP INTERACTION WITH GAB2.
RX PubMed=19172738; DOI=10.1038/emboj.2008.159;
RA Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P.,
RA Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D.,
RA Guilhaus M., James D.E., Daly R.J.;
RT "Phosphorylation-dependent binding of 14-3-3 terminates signalling by
RT the Gab2 docking protein.";
RL EMBO J. 27:2305-2316(2008).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [24]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [25]
RP INTERACTION WITH SRPK2.
RX PubMed=19592491; DOI=10.1074/jbc.M109.026237;
RA Jang S.W., Liu X., Fu H., Rees H., Yepes M., Levey A., Ye K.;
RT "Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell
RT cycle and cell death in neurons.";
RL J. Biol. Chem. 284:24512-24525(2009).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-50; LYS-69; LYS-118 AND
RP LYS-123, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-210, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [28]
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 [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-210, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1-233, MASS SPECTROMETRY,
RP INTERACTION WITH PHOSPHOSERINE MOTIFS, AND SUBUNIT.
RX PubMed=17085597; DOI=10.1073/pnas.0605779103;
RA Yang X., Lee W.H., Sobott F., Papagrigoriou E., Robinson C.V.,
RA Grossmann J.G., Sundstroem M., Doyle D.A., Elkins J.M.;
RT "Structural basis for protein-protein interactions in the 14-3-3
RT protein family.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:17237-17242(2006).
CC -!- FUNCTION: Adapter protein implicated in the regulation of a large
CC spectrum of both general and specialized signaling pathways. Binds
CC to a large number of partners, usually by recognition of a
CC phosphoserine or phosphothreonine motif. Binding generally results
CC in the modulation of the activity of the binding partner.
CC -!- SUBUNIT: Homodimer. Heterodimerizes with YWHAZ. Interacts with
CC NDEL1, ARHGEF28 and TIAM2 (By similarity). Interacts with HCV core
CC protein. Interacts with ABL1 (phosphorylated form); the
CC interaction retains it in the cytoplasm. Weakly interacts with
CC CDKN1B. Interacts with GAB2. Interacts with phosphorylated GRB10.
CC Interacts with PKA-phosphorylated AANAT. Interacts with the
CC phosphorylated (by AKT1) form of SRPK2.
CC -!- INTERACTION:
CC O14727:APAF1; NbExp=2; IntAct=EBI-356498, EBI-446492;
CC O00257-3:CBX4; NbExp=2; IntAct=EBI-356498, EBI-4392727;
CC O94921:CDK14; NbExp=3; IntAct=EBI-356498, EBI-1043945;
CC Q9UKT5:FBXO4; NbExp=5; IntAct=EBI-356498, EBI-960409;
CC P56524:HDAC4; NbExp=4; IntAct=EBI-356498, EBI-308629;
CC Q14678-2:KANK1; NbExp=3; IntAct=EBI-356498, EBI-6173812;
CC Q5S007:LRRK2; NbExp=4; IntAct=EBI-356498, EBI-5323863;
CC O15151:MDM4; NbExp=3; IntAct=EBI-356498, EBI-398437;
CC P58340:MLF1; NbExp=3; IntAct=EBI-356498, EBI-721328;
CC O35244:Prdx6 (xeno); NbExp=2; IntAct=EBI-356498, EBI-915490;
CC P61588:Rnd3 (xeno); NbExp=2; IntAct=EBI-356498, EBI-6930266;
CC Q99469:STAC; NbExp=2; IntAct=EBI-356498, EBI-2652799;
CC Q9GZV5:WWTR1; NbExp=3; IntAct=EBI-356498, EBI-747743;
CC P31946:YWHAB; NbExp=3; IntAct=EBI-356498, EBI-359815;
CC P61981:YWHAG; NbExp=4; IntAct=EBI-356498, EBI-359832;
CC P63104:YWHAZ; NbExp=5; IntAct=EBI-356498, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Melanosome.
CC Note=Identified by mass spectrometry in melanosome fractions from
CC stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P62258-1; Sequence=Displayed;
CC Name=SV;
CC IsoId=P62258-2; Sequence=VSP_040621;
CC Note=Unable to dimerize with YWHAZ;
CC -!- SIMILARITY: Belongs to the 14-3-3 family.
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DR EMBL; U20972; AAC50175.1; -; mRNA.
DR EMBL; U54778; AAC50710.1; -; mRNA.
DR EMBL; U43399; AAC50625.1; -; mRNA.
DR EMBL; U43430; AAD00026.1; -; mRNA.
DR EMBL; U28936; AAA75301.1; -; mRNA.
DR EMBL; AB017103; BAA32538.1; -; Genomic_DNA.
DR EMBL; AY883089; AAX68683.1; -; mRNA.
DR EMBL; AK128785; BAG54733.1; -; mRNA.
DR EMBL; AK295260; BAG58249.1; -; mRNA.
DR EMBL; AK316185; BAH14556.1; -; mRNA.
DR EMBL; BT007161; AAP35825.1; -; mRNA.
DR EMBL; CH471108; EAW90628.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90629.1; -; Genomic_DNA.
DR EMBL; BC000179; AAH00179.1; -; mRNA.
DR EMBL; BC001440; AAH01440.1; -; mRNA.
DR PIR; A61235; A61235.
DR PIR; I38947; I38947.
DR RefSeq; NP_006752.1; NM_006761.4.
DR UniGene; Hs.513851; -.
DR PDB; 2BR9; X-ray; 1.75 A; A=1-233.
DR PDB; 3UAL; X-ray; 1.80 A; A=1-232.
DR PDB; 3UBW; X-ray; 1.90 A; A=1-234.
DR PDBsum; 2BR9; -.
DR PDBsum; 3UAL; -.
DR PDBsum; 3UBW; -.
DR ProteinModelPortal; P62258; -.
DR SMR; P62258; 3-232.
DR DIP; DIP-36676N; -.
DR IntAct; P62258; 146.
DR MINT; MINT-4998623; -.
DR STRING; 9606.ENSP00000264335; -.
DR PhosphoSite; P62258; -.
DR DMDM; 51702210; -.
DR OGP; P42655; -.
DR UCD-2DPAGE; P62258; -.
DR PaxDb; P62258; -.
DR PeptideAtlas; P62258; -.
DR PRIDE; P62258; -.
DR DNASU; 7531; -.
DR Ensembl; ENST00000264335; ENSP00000264335; ENSG00000108953.
DR Ensembl; ENST00000571732; ENSP00000461762; ENSG00000108953.
DR GeneID; 7531; -.
DR KEGG; hsa:7531; -.
DR UCSC; uc002fsj.3; human.
DR CTD; 7531; -.
DR GeneCards; GC17M001148; -.
DR H-InvDB; HIX0013751; -.
DR H-InvDB; HIX0030006; -.
DR HGNC; HGNC:12851; YWHAE.
DR HPA; CAB016200; -.
DR HPA; CAB021109; -.
DR HPA; CAB047350; -.
DR HPA; HPA008445; -.
DR MIM; 605066; gene.
DR neXtProt; NX_P62258; -.
DR Orphanet; 217385; 17p13.3 microduplication syndrome.
DR Orphanet; 261257; Distal 17p13.3 microdeletion syndrome.
DR Orphanet; 531; Miller-Dieker syndrome.
DR PharmGKB; PA37440; -.
DR eggNOG; COG5040; -.
DR HOVERGEN; HBG050423; -.
DR InParanoid; P62258; -.
DR KO; K06630; -.
DR OMA; MQESDKP; -.
DR OrthoDB; EOG7HHWT3; -.
DR PhylomeDB; P62258; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; P62258; -.
DR ChiTaRS; YWHAE; human.
DR EvolutionaryTrace; P62258; -.
DR GeneWiki; YWHAE; -.
DR GenomeRNAi; 7531; -.
DR NextBio; 29461; -.
DR PMAP-CutDB; P62258; -.
DR PRO; PR:P62258; -.
DR ArrayExpress; P62258; -.
DR Bgee; P62258; -.
DR CleanEx; HS_YWHAE; -.
DR Genevestigator; P62258; -.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005871; C:kinesin complex; IEA:Ensembl.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0015459; F:potassium channel regulator activity; IDA:BHF-UCL.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0035329; P:hippo signaling cascade; TAS:Reactome.
DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0086013; P:membrane repolarization involved in regulation of cardiac muscle cell action potential; IC:BHF-UCL.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:1902309; P:negative regulation of peptidyl-serine dephosphorylation; IDA:BHF-UCL.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:1900740; P:positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0006605; P:protein targeting; IEA:Ensembl.
DR GO; GO:0043281; P:regulation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IC:BHF-UCL.
DR GO; GO:0003064; P:regulation of heart rate by hormone; NAS:BHF-UCL.
DR GO; GO:0060306; P:regulation of membrane repolarization; IDA:BHF-UCL.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL.
DR Gene3D; 1.20.190.20; -; 1.
DR InterPro; IPR000308; 14-3-3.
DR InterPro; IPR023409; 14-3-3_CS.
DR InterPro; IPR023410; 14-3-3_domain.
DR PANTHER; PTHR18860; PTHR18860; 1.
DR Pfam; PF00244; 14-3-3; 1.
DR PIRSF; PIRSF000868; 14-3-3; 1.
DR PRINTS; PR00305; 1433ZETA.
DR SMART; SM00101; 14_3_3; 1.
DR SUPFAM; SSF48445; SSF48445; 1.
DR PROSITE; PS00796; 1433_1; 1.
DR PROSITE; PS00797; 1433_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Host-virus interaction;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1 255 14-3-3 protein epsilon.
FT /FTId=PRO_0000058618.
FT SITE 57 57 Interaction with phosphoserine on
FT interacting protein.
FT SITE 130 130 Interaction with phosphoserine on
FT interacting protein.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 50 50 N6-acetyllysine.
FT MOD_RES 69 69 N6-acetyllysine.
FT MOD_RES 118 118 N6-acetyllysine.
FT MOD_RES 123 123 N6-acetyllysine.
FT MOD_RES 210 210 Phosphoserine.
FT VAR_SEQ 1 22 Missing (in isoform SV).
FT /FTId=VSP_040621.
FT CONFLICT 106 107 KH -> NY (in Ref. 13; AA sequence).
FT CONFLICT 143 143 E -> F (in Ref. 13; AA sequence).
FT CONFLICT 148 148 S -> T (in Ref. 13; AA sequence).
FT HELIX 4 17
FT HELIX 20 31
FT HELIX 39 73
FT HELIX 76 106
FT HELIX 108 111
FT HELIX 115 135
FT HELIX 138 162
FT HELIX 168 183
FT HELIX 188 204
FT HELIX 205 208
FT TURN 211 213
FT HELIX 214 231
SQ SEQUENCE 255 AA; 29174 MW; 07817CCBD1F75B26 CRC64;
MDDREDLVYQ AKLAEQAERY DEMVESMKKV AGMDVELTVE ERNLLSVAYK NVIGARRASW
RIISSIEQKE ENKGGEDKLK MIREYRQMVE TELKLICCDI LDVLDKHLIP AANTGESKVF
YYKMKGDYHR YLAEFATGND RKEAAENSLV AYKAASDIAM TELPPTHPIR LGLALNFSVF
YYEILNSPDR ACRLAKAAFD DAIAELDTLS EESYKDSTLI MQLLRDNLTL WTSDMQGDGE
EQNKEALQDV EDENQ
//
MIM
605066
*RECORD*
*FIELD* NO
605066
*FIELD* TI
*605066 TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN,
EPSILON ISOFORM; YWHAE
read more;;14-3-3 PROTEIN, EPSILON ISOFORM;;
14-3-3-EPSILON
*FIELD* TX
CLONING
Cell division cycle (CDC) proteins and cyclin-dependent kinases (CDK)
regulate the progression of cells through mitosis, and their activities
are regulated by phosphorylation and dephosphorylation. Interacting
proteins can also affect CDC and CDK activity. Using a yeast 2-hybrid
screen to probe a HeLa cell library with CDC25A (116947) and CDC25B
(116949) as bait, Conklin et al. (1995) isolated cDNAs encoding YWHAB
(601289), which they called 14-3-3-beta, and YWHAE, which they called
14-3-3-epsilon. The deduced YWHAE contains 260-amino acids that are 100%
identical to those of the mouse protein.
Chong et al. (1996) isolated a full-length YWHAE cDNA. Sequence analysis
predicted a 255-amino acid protein. Northern blot analysis revealed
nearly ubiquitous expression of an approximately 2.0-kb transcript.
GENE STRUCTURE
Jin et al. (1996) obtained a YWHAE cDNA containing the previously
unreported 3-prime untranslated region (UTR), which is perfectly
conserved with rodent sequences. The 3-prime UTR included a 285-bp match
with the 8-1 probe for Miller-Dieker lissencephaly syndrome (MDLS;
247200). The authors concluded that the 3-prime YWHAE UTR and the
5-prime end of the MDLS region overlap. However, Chong et al. (1996)
determined that the 8.1 probe was a chimeric cDNA and did not include
the 5-prime end of the LIS1 (PAFAH2B1; 601545) gene.
MAPPING
By radiation hybrid, PCR, and FISH analyses, Chong et al. (1996) mapped
the human YWHAE gene to 17p13.3, telomeric to LIS1 (PAFAH1B1), in a
region frequently deleted in several types of cancer. Luk et al. (1997)
confirmed this localization by FISH.
Using RFLP analysis, Jin et al. (1996) mapped the mouse Ywhae gene to a
position in tight linkage with Evi2 (158380).
GENE FUNCTION
Conklin et al. (1995) found that both YWHAB and YWHAE interacted with
CDC25A and CDC25B but did not affect their phosphatase activities. Like
YWHAB, YWHAE interacted with RAF1 (164760) but not RAS (190020) in yeast
2-hybrid screens and may facilitate the association of CDC25 with RAF1.
The binding of insulin (176730) to its receptor induces the
phosphorylation of the cytosolic substrates IRS1 (147545) and IRS2
(600797), which associate with several Src homology-2 (SH2)
domain-containing proteins. To identify unique IRS1-binding proteins,
Ogihara et al. (1997) screened a human heart cDNA expression library
with recombinant IRS1. They obtained 2 isoforms of the 14-3-3 protein
family, 14-3-3-zeta (YWHAZ; 601288) and -epsilon. 14-3-3 protein has
been shown to associate with IRS1 in L6 myotubes, HepG2 hepatoma cells,
Chinese hamster ovary cells, and bovine brain tissue. IRS2, a protein
structurally similar to IRS1, was also shown to form a complex with
14-3-3 protein using a baculovirus expression system. The amount of
14-3-3 protein associated with IRS1 was not affected by insulin
stimulation but was increased significantly by treatment with okadaic
acid, a potent serine/threonine phosphatase inhibitor. The authors
identified a putative 14-3-3 protein-binding site within the
phosphotyrosine-binding (PTB) domain of IRS1. Ogihara et al. (1997)
suggested that the association with 14-3-3 protein may play a role in
the regulation of insulin sensitivity by interrupting the association
between the insulin receptor and IRS1.
Using 2-hybrid experiments, Han et al. (1997) demonstrated interaction
between murine Ywhae and the RAS-binding domain of RIN1 (605965).
Toyo-oka et al. (2003) reported that mice deficient in the 14-3-3
epsilon protein have defects in brain development and neuronal
migration, similar to defects observed in mice heterozygous with regard
to Pafah1b1 (601545), the gene that is associated with isolated
lissencephaly (ILS; 607432). Mice heterozygous with respect to both
Pafah1b1 and Ywhae have more severe migration defects than single
heterozygotes. 14-3-3-epsilon binds to NUDEL (607538) phosphorylated by
CDK/p35 (CDK5R1; 603460), and this binding maintains NUDEL
phosphorylation. Similar to PAFAH1B1, deficiency of 14-3-3-epsilon
results in mislocalization of NUDEL and PAFAH1B1, consistent with
reduction of cytoplasmic dynein function. These results established a
crucial role for 14-3-3-epsilon in neuronal development by sustaining
the effects of CDK5 (123831) phosphorylation and provided a molecular
explanation for the differences in severity of human neuronal migration
defects, including MDLS, that are associated with 17p13.3 deletions.
In cellular studies and in rat brain, Taya et al. (2007) found that
YWHAE interacted with DISC1 (605210) in a complex with NUDEL and LIS1 in
cell bodies and in the distal part of axons. DISC1 directly interacted
with kinesin-1, a large tetramer of anterograde axonal transport, and
also partially colocalized with kinesin family member 5A (KIF5A;
602821), NUDEL, LIS1, and YWHAE in the growth cones of rat hippocampal
neurons. Knockdown of these proteins inhibited axon elongation. The
findings indicated that DISC1 regulates the localization of
NUDEL1/LIS1/YWHAE into axons as a cargo receptor for axon elongation.
Wang et al. (2012) showed that beclin-1 (604378), an essential autophagy
and tumor suppressor protein, is a target of the protein kinase AKT
(164730). Expression of a beclin-1 mutant resistant to Akt-mediated
phosphorylation increased autophagy, reduced anchorage-independent
growth, and inhibited Akt-driven tumorigenesis. Akt-mediated
phosphorylation of beclin-1 enhanced its interactions with 14-3-3 and
vimentin (193060) intermediate filament proteins, and vimentin depletion
increased autophagy and inhibited Akt-driven transformation. Thus, Wang
et al. (2012) concluded that Akt-mediated phosphorylation of beclin-1
functions in autophagy inhibition, oncogenesis, and the formation of an
autophagy-inhibitory beclin-1/14-3-3/vimentin intermediate filament
complex, and suggested their findings have broad implications for
understanding the role of Akt signaling and intermediate filament
proteins in autophagy and cancer.
CYTOGENETICS
Cardoso et al. (2003) completed a physical and transcriptional map of
the 17p13.3 region from LIS1 (PAFAH1B1; 601545) to the telomere. Using
FISH, they mapped the deletion size in 19 children with isolated
lissencephaly (ILS; 607432), 11 children with Miller-Dieker syndrome
(MDS; 247200), and 4 children with 17p13.3 deletions not involving LIS1.
They showed that the critical region that differentiates ILS from MDS at
the molecular level can be reduced to 400 kb. Using somatic cell hybrids
from selected patients, Cardoso et al. (2003) identified 8 genes
consistently deleted in patients classified as having MDS: PRP8
(607300), RILP (607848), SREC (SCARF1; 607873), PITPNA (600174), SKIP
(603055), MYO1C (606538), CRK (164762), and 14-3-3-epsilon (605066).
These genes defined the telomeric MDS critical region, which contains
additional genes distal to LIS1 that are responsible for the clinical
features that distinguish MDS from ILS. In addition, deletion of the CRK
and YWHAE genes delineated patients with the most severe lissencephaly
grade. Deletion of the ABR gene (600365), which is outside the MDS
critical region, was associated with no apparent phenotype. On the basis
of recent functional data and the creation of a mouse model suggesting a
role for 14-3-3-epsilon in cortical development, Cardoso et al. (2003)
suggested that deletion of one or both of these genes in combination
with deletion of PAFAH1B1 may contribute to the more severe form of
lissencephaly seen only in patients with Miller-Dieker lissencephaly
syndrome.
Bi et al. (2009) reported 7 unrelated individuals with different
submicroscopic duplications of 17p13.3 (613215) involving the LIS1
and/or the YWHAE gene. Four individuals had a duplication of YWHAE but
not LIS1, and 1 had a duplication of LIS1, but not YWHAE. A sixth
patient had a triplication of LIS1, and a seventh had duplication of
both genes. Analysis of the clinical features for each individual
indicated that individuals with LIS1 duplications had subtle brain
defects, including microcephaly, dysgenesis of the corpus callosum, and
cerebellar atrophy, as well as neurobehavioral disorders, including
delayed development, mental retardation, and attention
deficit-hyperactivity disorder. Patients with duplications of YWHAE
tended to have macrosomia, facial dysmorphism, and mild developmental
delay.
Mignon-Ravix et al. (2010) reported a patient with developmental delay
and facial dysmorphism who was found to have a heterozygous deletion of
394 to 411 kb on chromosome 17p13.3. At age 3 years 7 months, he had
macrocephaly and facial anomalies reminiscent of MDS, including high
forehead with bitemporal hollowing, hypertelorism, epicanthus,
downslanting palpebral fissures, anteverted nares, pronounced cupid bow,
and small low-set posteriorly rotated ears with irregular helices. Brain
MRI showed pronounced hypoplasia of the corpus callosum with posterior
agenesis and ependymal and periventricular nodular heterotopias, mostly
in the occipital areas. Anterior regions displayed malformation of
cortical development with polymicrogyric like appearance of the frontal
lobes associated with foci of pachygyria and subcortical heterotopias.
The deleted region contained 5 genes: TIMM22 (607251), ABR, BHLHA9
(615416), TUSC5 (612211) and YWHAE, but only haploinsufficiency of YWHAE
was considered to be pathogenic. Mignon-Ravix et al. (2010) noted that
the phenotype was similar to that described in heterozygous
Ywhae-deficient mice by Toyo-oka et al., 2003.
MOLECULAR GENETICS
Among 1,429 Japanese patients with schizophrenia (181500) and 1,728
controls, Ikeda et al. (2008) found a significant association between a
G-to-C SNP (dbSNP rs28365859) in the 5-prime flanking region of the
YWHAE gene, -261 bp from the initial exon, and schizophrenia. Controls
had a significantly higher frequency of the minor C allele compared to
patients (p = 1.01 x 10(-5)). The region in which this SNP is located is
not highly conserved. In vitro functional expression studies showed that
the minor C allele was associated with higher gene expression, and YWHAE
mRNA and protein levels were higher in peripheral blood samples of C
allele carriers compared to G allele carriers. An odds ratio of 0.76 was
associated with the C allele, suggesting a protective effect. Ikeda et
al. (2008) demonstrated that heterozygous Ywhae mice had weak defects in
working memory and increased anxiety-like behavior. Overall, the
findings suggested that YWHAE may be a susceptibility gene for
schizophrenia. The YWHAE gene was studied because of its interaction
with DISC1 (605210), which has been implicated in schizophrenia.
ANIMAL MODEL
Toyo-oka et al. (2003) reported that mice deficient in the 14-3-3
epsilon protein have defects in brain development and neuronal
migration, similar to defects observed in mice heterozygous with regard
to Pafah1b1 (601545), the gene that is associated with isolated
lissencephaly (ILS; 607432). Mice heterozygous with respect to both
Pafah1b1 and Ywhae have more severe migration defects than single
heterozygotes.
Ikeda et al. (2008) found that Ywhae-null mice had severe migration
defects in the cortex and hippocampus compared to controls and died
shortly after birth. Ywhae heterozygous mice showed milder migration
defects, mild defects in spatial working memory, and possibly enhanced
anxiety in an elevated plus-maze test. However, mutant mice did not show
a change in prepulse inhibition compared to controls.
*FIELD* RF
1. Bi, W.; Sapir, T.; Shchelochkov, O. A.; Zhang, F.; Withers, M.
A.; Hunter, J. V.; Levy, T.; Shinder, V.; Peiffer, D. A.; Gunderson,
K. L.; Nezarati, M. M.; Shotts, V. A.; and 13 others: Increased
LIS1 expression affects human and mouse brain development. Nature
Genet. 41: 168-177, 2009.
2. Cardoso, C.; Leventer, R. J.; Ward, H. L.; Toyo-oka, K.; Chung,
J.; Gross, A.; Martin, C. L.; Allanson, J.; Pilz, D. T.; Olney, A.
H.; Mutchinick, O. M.; Hirotsune, S.; Wynshaw-Boris, A.; Dobyns, W.
B.; Ledbetter, D. H.: Refinement of a 400-kb critical region allows
genotypic differentiation between isolated lissencephaly, Miller-Dieker
syndrome, and other phenotypes secondary to deletions of 17p13.3. Am.
J. Hum. Genet. 72: 918-930, 2003.
3. Chong, S. S.; Tanigami, A.; Roschke, A. V.; Ledbetter, D. H.:
14-3-3-epsilon has no homology to LIS1 and lies telomeric to it on
chromosome 17p13.3 outside the Miller-Dieker syndrome chromosome region. Genome
Res. 6: 735-741, 1996.
4. Conklin, D. S.; Galaktionov, K.; Beach, D.: 14-3-3 proteins associate
with cdc25 phosphatases. Proc. Nat. Acad. Sci. 92: 7892-7896, 1995.
5. Han, L. Wong, D.; Dhaka, A.; Afar, D.; White, M.; Xie, W.; Herschman,
H.; Witte, O.: Colicelli, J.: Protein binding and signaling properties
of RIN1 suggest a unique effector function. Proc. Nat. Acad. Sci. 94:
4954-4959, 1997.
6. Ikeda, M.; Hikita, T.; Taya, S.; Uraguchi-Asaki, J.; Toyo-oka,
K.; Wynshaw-Boris, A.; Ujike, H.; Inada, T.; Takao, K.; Miyakawa,
T.; Ozaki, N.; Kaibuchi, K.; Iwata, N.: Identification of YWHAE,
a gene encoding 14-3-3epsilon, as a possible susceptibility gene for
schizophrenia. Hum. Molec. Genet. 17: 3212-3222, 2008.
7. Jin, D.-Y.; Lyu, M. S.; Kozak, C. A.; Jeang, K.-T.: Function of
14-3-3 proteins. Nature 382: 308 only, 1996.
8. Luk, S. C. W.; Garcia-Barcelo, M.; Tsui, S. K. W.; Fung, K. P.;
Lee, C. Y.; Waye, M. M. Y.: Assignment of the human 14-3-3 epsilon
isoform (YWHAE) to human chromosome 17p13 by in situ hybridization. Cytogenet.
Cell Genet. 78: 105-106, 1997.
9. Mignon-Ravix, C.; Cacciagli, P.; El-Waly, B.; Moncla, A.; Milh,
M.; Girard, N.; Chabrol, B.; Philip, N.; Villard, L.: Deletion of
YWHAE in a patient with periventricular heterotopias and pronounced
corpus callosum hypoplasia. J. Med. Genet. 47: 132-136, 2010.
10. Ogihara, T.; Isobe, T.; Ichimura, T.; Taoka, M.; Funaki, M.; Sakoda,
H.; Onishi, Y.; Inukai, K.; Anai, M.; Fukushima, Y.; Kikuchi, M.;
Yazaki, Y.; Oka, Y.; Asano, T.: 14-3-3 protein binds to insulin receptor
substrate-1, one of the binding sites of which is in the phosphotyrosine
binding domain. J. Biol. Chem. 272: 25267-25274, 1997.
11. Taya, S.; Shinoda, T.; Tsuboi, D.; Asaki, J.; Nagai, K.; Hikita,
T.; Kuroda, S.; Kuroda, K.; Shimizu, M.; Hirotsune, S.; Iwamatsu,
A.; Kaibuchi, K.: DISC1 regulates the transport of the NUDEL/LIS1/14-3-3-epsilon
complex through kinesin-1. J. Neurosci. 27: 15-26, 2007.
12. Toyo-oka, K.; Shionoya, A.; Gambello, M. J.; Cardoso, C.; Leventer,
R.; Ward, H. L.; Ayala, R.; Tsai, L.-H.; Dobyns, W.; Ledbetter, D.;
Hirotsune, S.; Wynshaw-Boris, A.: 14-3-3-epsilon is important for
neuronal migration by binding to NUDEL: a molecular explanation for
Miller-Dieker syndrome. Nature Genet. 34: 274-285, 2003.
13. Wang, R. C.; Wei, Y.; An, Z.; Zou, Z.; Xiao, G.; Bhagat, G.; White,
M.; Reichelt, J.; Levine, B.: Akt-mediated regulation of autophagy
and tumorigenesis through beclin 1 phosphorylation. Science 338:
956-959, 2012.
*FIELD* CN
Ada Hamosh - updated: 1/7/2013
Cassandra L. Kniffin - updated: 3/27/2012
Cassandra L. Kniffin - updated: 6/3/2010
Cassandra L. Kniffin - updated: 3/10/2009
Victor A. McKusick - updated: 6/9/2003
Ada Hamosh - updated: 5/9/2003
Dawn Watkins-Chow - updated: 5/25/2001
Paul J. Converse - updated: 11/6/2000
*FIELD* CD
Patti M. Sherman: 6/22/2000
*FIELD* ED
mgross: 09/16/2013
alopez: 1/7/2013
terry: 1/7/2013
alopez: 4/2/2012
terry: 3/28/2012
ckniffin: 3/27/2012
wwang: 6/9/2010
ckniffin: 6/3/2010
carol: 1/12/2010
ckniffin: 1/12/2010
alopez: 3/11/2009
ckniffin: 3/10/2009
carol: 8/28/2008
alopez: 7/29/2003
alopez: 6/10/2003
terry: 6/9/2003
cwells: 5/13/2003
terry: 5/9/2003
carol: 5/25/2001
mgross: 11/6/2000
mcapotos: 6/23/2000
psherman: 6/22/2000
*RECORD*
*FIELD* NO
605066
*FIELD* TI
*605066 TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN,
EPSILON ISOFORM; YWHAE
read more;;14-3-3 PROTEIN, EPSILON ISOFORM;;
14-3-3-EPSILON
*FIELD* TX
CLONING
Cell division cycle (CDC) proteins and cyclin-dependent kinases (CDK)
regulate the progression of cells through mitosis, and their activities
are regulated by phosphorylation and dephosphorylation. Interacting
proteins can also affect CDC and CDK activity. Using a yeast 2-hybrid
screen to probe a HeLa cell library with CDC25A (116947) and CDC25B
(116949) as bait, Conklin et al. (1995) isolated cDNAs encoding YWHAB
(601289), which they called 14-3-3-beta, and YWHAE, which they called
14-3-3-epsilon. The deduced YWHAE contains 260-amino acids that are 100%
identical to those of the mouse protein.
Chong et al. (1996) isolated a full-length YWHAE cDNA. Sequence analysis
predicted a 255-amino acid protein. Northern blot analysis revealed
nearly ubiquitous expression of an approximately 2.0-kb transcript.
GENE STRUCTURE
Jin et al. (1996) obtained a YWHAE cDNA containing the previously
unreported 3-prime untranslated region (UTR), which is perfectly
conserved with rodent sequences. The 3-prime UTR included a 285-bp match
with the 8-1 probe for Miller-Dieker lissencephaly syndrome (MDLS;
247200). The authors concluded that the 3-prime YWHAE UTR and the
5-prime end of the MDLS region overlap. However, Chong et al. (1996)
determined that the 8.1 probe was a chimeric cDNA and did not include
the 5-prime end of the LIS1 (PAFAH2B1; 601545) gene.
MAPPING
By radiation hybrid, PCR, and FISH analyses, Chong et al. (1996) mapped
the human YWHAE gene to 17p13.3, telomeric to LIS1 (PAFAH1B1), in a
region frequently deleted in several types of cancer. Luk et al. (1997)
confirmed this localization by FISH.
Using RFLP analysis, Jin et al. (1996) mapped the mouse Ywhae gene to a
position in tight linkage with Evi2 (158380).
GENE FUNCTION
Conklin et al. (1995) found that both YWHAB and YWHAE interacted with
CDC25A and CDC25B but did not affect their phosphatase activities. Like
YWHAB, YWHAE interacted with RAF1 (164760) but not RAS (190020) in yeast
2-hybrid screens and may facilitate the association of CDC25 with RAF1.
The binding of insulin (176730) to its receptor induces the
phosphorylation of the cytosolic substrates IRS1 (147545) and IRS2
(600797), which associate with several Src homology-2 (SH2)
domain-containing proteins. To identify unique IRS1-binding proteins,
Ogihara et al. (1997) screened a human heart cDNA expression library
with recombinant IRS1. They obtained 2 isoforms of the 14-3-3 protein
family, 14-3-3-zeta (YWHAZ; 601288) and -epsilon. 14-3-3 protein has
been shown to associate with IRS1 in L6 myotubes, HepG2 hepatoma cells,
Chinese hamster ovary cells, and bovine brain tissue. IRS2, a protein
structurally similar to IRS1, was also shown to form a complex with
14-3-3 protein using a baculovirus expression system. The amount of
14-3-3 protein associated with IRS1 was not affected by insulin
stimulation but was increased significantly by treatment with okadaic
acid, a potent serine/threonine phosphatase inhibitor. The authors
identified a putative 14-3-3 protein-binding site within the
phosphotyrosine-binding (PTB) domain of IRS1. Ogihara et al. (1997)
suggested that the association with 14-3-3 protein may play a role in
the regulation of insulin sensitivity by interrupting the association
between the insulin receptor and IRS1.
Using 2-hybrid experiments, Han et al. (1997) demonstrated interaction
between murine Ywhae and the RAS-binding domain of RIN1 (605965).
Toyo-oka et al. (2003) reported that mice deficient in the 14-3-3
epsilon protein have defects in brain development and neuronal
migration, similar to defects observed in mice heterozygous with regard
to Pafah1b1 (601545), the gene that is associated with isolated
lissencephaly (ILS; 607432). Mice heterozygous with respect to both
Pafah1b1 and Ywhae have more severe migration defects than single
heterozygotes. 14-3-3-epsilon binds to NUDEL (607538) phosphorylated by
CDK/p35 (CDK5R1; 603460), and this binding maintains NUDEL
phosphorylation. Similar to PAFAH1B1, deficiency of 14-3-3-epsilon
results in mislocalization of NUDEL and PAFAH1B1, consistent with
reduction of cytoplasmic dynein function. These results established a
crucial role for 14-3-3-epsilon in neuronal development by sustaining
the effects of CDK5 (123831) phosphorylation and provided a molecular
explanation for the differences in severity of human neuronal migration
defects, including MDLS, that are associated with 17p13.3 deletions.
In cellular studies and in rat brain, Taya et al. (2007) found that
YWHAE interacted with DISC1 (605210) in a complex with NUDEL and LIS1 in
cell bodies and in the distal part of axons. DISC1 directly interacted
with kinesin-1, a large tetramer of anterograde axonal transport, and
also partially colocalized with kinesin family member 5A (KIF5A;
602821), NUDEL, LIS1, and YWHAE in the growth cones of rat hippocampal
neurons. Knockdown of these proteins inhibited axon elongation. The
findings indicated that DISC1 regulates the localization of
NUDEL1/LIS1/YWHAE into axons as a cargo receptor for axon elongation.
Wang et al. (2012) showed that beclin-1 (604378), an essential autophagy
and tumor suppressor protein, is a target of the protein kinase AKT
(164730). Expression of a beclin-1 mutant resistant to Akt-mediated
phosphorylation increased autophagy, reduced anchorage-independent
growth, and inhibited Akt-driven tumorigenesis. Akt-mediated
phosphorylation of beclin-1 enhanced its interactions with 14-3-3 and
vimentin (193060) intermediate filament proteins, and vimentin depletion
increased autophagy and inhibited Akt-driven transformation. Thus, Wang
et al. (2012) concluded that Akt-mediated phosphorylation of beclin-1
functions in autophagy inhibition, oncogenesis, and the formation of an
autophagy-inhibitory beclin-1/14-3-3/vimentin intermediate filament
complex, and suggested their findings have broad implications for
understanding the role of Akt signaling and intermediate filament
proteins in autophagy and cancer.
CYTOGENETICS
Cardoso et al. (2003) completed a physical and transcriptional map of
the 17p13.3 region from LIS1 (PAFAH1B1; 601545) to the telomere. Using
FISH, they mapped the deletion size in 19 children with isolated
lissencephaly (ILS; 607432), 11 children with Miller-Dieker syndrome
(MDS; 247200), and 4 children with 17p13.3 deletions not involving LIS1.
They showed that the critical region that differentiates ILS from MDS at
the molecular level can be reduced to 400 kb. Using somatic cell hybrids
from selected patients, Cardoso et al. (2003) identified 8 genes
consistently deleted in patients classified as having MDS: PRP8
(607300), RILP (607848), SREC (SCARF1; 607873), PITPNA (600174), SKIP
(603055), MYO1C (606538), CRK (164762), and 14-3-3-epsilon (605066).
These genes defined the telomeric MDS critical region, which contains
additional genes distal to LIS1 that are responsible for the clinical
features that distinguish MDS from ILS. In addition, deletion of the CRK
and YWHAE genes delineated patients with the most severe lissencephaly
grade. Deletion of the ABR gene (600365), which is outside the MDS
critical region, was associated with no apparent phenotype. On the basis
of recent functional data and the creation of a mouse model suggesting a
role for 14-3-3-epsilon in cortical development, Cardoso et al. (2003)
suggested that deletion of one or both of these genes in combination
with deletion of PAFAH1B1 may contribute to the more severe form of
lissencephaly seen only in patients with Miller-Dieker lissencephaly
syndrome.
Bi et al. (2009) reported 7 unrelated individuals with different
submicroscopic duplications of 17p13.3 (613215) involving the LIS1
and/or the YWHAE gene. Four individuals had a duplication of YWHAE but
not LIS1, and 1 had a duplication of LIS1, but not YWHAE. A sixth
patient had a triplication of LIS1, and a seventh had duplication of
both genes. Analysis of the clinical features for each individual
indicated that individuals with LIS1 duplications had subtle brain
defects, including microcephaly, dysgenesis of the corpus callosum, and
cerebellar atrophy, as well as neurobehavioral disorders, including
delayed development, mental retardation, and attention
deficit-hyperactivity disorder. Patients with duplications of YWHAE
tended to have macrosomia, facial dysmorphism, and mild developmental
delay.
Mignon-Ravix et al. (2010) reported a patient with developmental delay
and facial dysmorphism who was found to have a heterozygous deletion of
394 to 411 kb on chromosome 17p13.3. At age 3 years 7 months, he had
macrocephaly and facial anomalies reminiscent of MDS, including high
forehead with bitemporal hollowing, hypertelorism, epicanthus,
downslanting palpebral fissures, anteverted nares, pronounced cupid bow,
and small low-set posteriorly rotated ears with irregular helices. Brain
MRI showed pronounced hypoplasia of the corpus callosum with posterior
agenesis and ependymal and periventricular nodular heterotopias, mostly
in the occipital areas. Anterior regions displayed malformation of
cortical development with polymicrogyric like appearance of the frontal
lobes associated with foci of pachygyria and subcortical heterotopias.
The deleted region contained 5 genes: TIMM22 (607251), ABR, BHLHA9
(615416), TUSC5 (612211) and YWHAE, but only haploinsufficiency of YWHAE
was considered to be pathogenic. Mignon-Ravix et al. (2010) noted that
the phenotype was similar to that described in heterozygous
Ywhae-deficient mice by Toyo-oka et al., 2003.
MOLECULAR GENETICS
Among 1,429 Japanese patients with schizophrenia (181500) and 1,728
controls, Ikeda et al. (2008) found a significant association between a
G-to-C SNP (dbSNP rs28365859) in the 5-prime flanking region of the
YWHAE gene, -261 bp from the initial exon, and schizophrenia. Controls
had a significantly higher frequency of the minor C allele compared to
patients (p = 1.01 x 10(-5)). The region in which this SNP is located is
not highly conserved. In vitro functional expression studies showed that
the minor C allele was associated with higher gene expression, and YWHAE
mRNA and protein levels were higher in peripheral blood samples of C
allele carriers compared to G allele carriers. An odds ratio of 0.76 was
associated with the C allele, suggesting a protective effect. Ikeda et
al. (2008) demonstrated that heterozygous Ywhae mice had weak defects in
working memory and increased anxiety-like behavior. Overall, the
findings suggested that YWHAE may be a susceptibility gene for
schizophrenia. The YWHAE gene was studied because of its interaction
with DISC1 (605210), which has been implicated in schizophrenia.
ANIMAL MODEL
Toyo-oka et al. (2003) reported that mice deficient in the 14-3-3
epsilon protein have defects in brain development and neuronal
migration, similar to defects observed in mice heterozygous with regard
to Pafah1b1 (601545), the gene that is associated with isolated
lissencephaly (ILS; 607432). Mice heterozygous with respect to both
Pafah1b1 and Ywhae have more severe migration defects than single
heterozygotes.
Ikeda et al. (2008) found that Ywhae-null mice had severe migration
defects in the cortex and hippocampus compared to controls and died
shortly after birth. Ywhae heterozygous mice showed milder migration
defects, mild defects in spatial working memory, and possibly enhanced
anxiety in an elevated plus-maze test. However, mutant mice did not show
a change in prepulse inhibition compared to controls.
*FIELD* RF
1. Bi, W.; Sapir, T.; Shchelochkov, O. A.; Zhang, F.; Withers, M.
A.; Hunter, J. V.; Levy, T.; Shinder, V.; Peiffer, D. A.; Gunderson,
K. L.; Nezarati, M. M.; Shotts, V. A.; and 13 others: Increased
LIS1 expression affects human and mouse brain development. Nature
Genet. 41: 168-177, 2009.
2. Cardoso, C.; Leventer, R. J.; Ward, H. L.; Toyo-oka, K.; Chung,
J.; Gross, A.; Martin, C. L.; Allanson, J.; Pilz, D. T.; Olney, A.
H.; Mutchinick, O. M.; Hirotsune, S.; Wynshaw-Boris, A.; Dobyns, W.
B.; Ledbetter, D. H.: Refinement of a 400-kb critical region allows
genotypic differentiation between isolated lissencephaly, Miller-Dieker
syndrome, and other phenotypes secondary to deletions of 17p13.3. Am.
J. Hum. Genet. 72: 918-930, 2003.
3. Chong, S. S.; Tanigami, A.; Roschke, A. V.; Ledbetter, D. H.:
14-3-3-epsilon has no homology to LIS1 and lies telomeric to it on
chromosome 17p13.3 outside the Miller-Dieker syndrome chromosome region. Genome
Res. 6: 735-741, 1996.
4. Conklin, D. S.; Galaktionov, K.; Beach, D.: 14-3-3 proteins associate
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5. Han, L. Wong, D.; Dhaka, A.; Afar, D.; White, M.; Xie, W.; Herschman,
H.; Witte, O.: Colicelli, J.: Protein binding and signaling properties
of RIN1 suggest a unique effector function. Proc. Nat. Acad. Sci. 94:
4954-4959, 1997.
6. Ikeda, M.; Hikita, T.; Taya, S.; Uraguchi-Asaki, J.; Toyo-oka,
K.; Wynshaw-Boris, A.; Ujike, H.; Inada, T.; Takao, K.; Miyakawa,
T.; Ozaki, N.; Kaibuchi, K.; Iwata, N.: Identification of YWHAE,
a gene encoding 14-3-3epsilon, as a possible susceptibility gene for
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7. Jin, D.-Y.; Lyu, M. S.; Kozak, C. A.; Jeang, K.-T.: Function of
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8. Luk, S. C. W.; Garcia-Barcelo, M.; Tsui, S. K. W.; Fung, K. P.;
Lee, C. Y.; Waye, M. M. Y.: Assignment of the human 14-3-3 epsilon
isoform (YWHAE) to human chromosome 17p13 by in situ hybridization. Cytogenet.
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9. Mignon-Ravix, C.; Cacciagli, P.; El-Waly, B.; Moncla, A.; Milh,
M.; Girard, N.; Chabrol, B.; Philip, N.; Villard, L.: Deletion of
YWHAE in a patient with periventricular heterotopias and pronounced
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H.; Onishi, Y.; Inukai, K.; Anai, M.; Fukushima, Y.; Kikuchi, M.;
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T.; Kuroda, S.; Kuroda, K.; Shimizu, M.; Hirotsune, S.; Iwamatsu,
A.; Kaibuchi, K.: DISC1 regulates the transport of the NUDEL/LIS1/14-3-3-epsilon
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*FIELD* CN
Ada Hamosh - updated: 1/7/2013
Cassandra L. Kniffin - updated: 3/27/2012
Cassandra L. Kniffin - updated: 6/3/2010
Cassandra L. Kniffin - updated: 3/10/2009
Victor A. McKusick - updated: 6/9/2003
Ada Hamosh - updated: 5/9/2003
Dawn Watkins-Chow - updated: 5/25/2001
Paul J. Converse - updated: 11/6/2000
*FIELD* CD
Patti M. Sherman: 6/22/2000
*FIELD* ED
mgross: 09/16/2013
alopez: 1/7/2013
terry: 1/7/2013
alopez: 4/2/2012
terry: 3/28/2012
ckniffin: 3/27/2012
wwang: 6/9/2010
ckniffin: 6/3/2010
carol: 1/12/2010
ckniffin: 1/12/2010
alopez: 3/11/2009
ckniffin: 3/10/2009
carol: 8/28/2008
alopez: 7/29/2003
alopez: 6/10/2003
terry: 6/9/2003
cwells: 5/13/2003
terry: 5/9/2003
carol: 5/25/2001
mgross: 11/6/2000
mcapotos: 6/23/2000
psherman: 6/22/2000