Full text data of SFN
SFN
(HME1)
[Confidence: low (only semi-automatic identification from reviews)]
14-3-3 protein sigma (Epithelial cell marker protein 1; Stratifin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
14-3-3 protein sigma (Epithelial cell marker protein 1; Stratifin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P31947
ID 1433S_HUMAN Reviewed; 248 AA.
AC P31947; Q6FH30; Q6FH51; Q96DH0;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1993, sequence version 1.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=14-3-3 protein sigma;
DE AltName: Full=Epithelial cell marker protein 1;
DE AltName: Full=Stratifin;
GN Name=SFN; Synonyms=HME1;
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=Epithelium;
RX PubMed=1390337;
RA Prasad G.L., Valverius E.M., McDuffie E., Cooper H.L.;
RT "Complementary DNA cloning of a novel epithelial cell marker protein,
RT HME1, that may be down-regulated in neoplastic mammary cells.";
RL Cell Growth Differ. 3:507-513(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 19-25;
RP 42-49; 118-122; 130-139; 149-159; 161-181; 196-199; 225-229 AND
RP 231-239.
RC TISSUE=Keratinocyte;
RX PubMed=8515476; DOI=10.1006/jmbi.1993.1346;
RA Leffers H., Madsen P., Rasmussen H.H., Honore B., Andersen A.H.,
RA Walbum E., Vandekerckhove J., Celis J.E.;
RT "Molecular cloning and expression of the transformation sensitive
RT epithelial marker stratifin. A member of a protein family that has
RT been involved in the protein kinase C signalling pathway.";
RL J. Mol. Biol. 231:982-998(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=9659898; DOI=10.1016/S1097-2765(00)80002-7;
RA Hermeking H., Lengauer C., Polyak K., He T.-C., Zhang L.,
RA Thiagalingam S., Kinzler K.W., Vogelstein B.;
RT "14-3-3 sigma is a p53-regulated inhibitor of G2/M progression.";
RL Mol. Cell 1:3-11(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cervix, Lung, and 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 [7]
RP PROTEIN SEQUENCE OF 42-49 AND 118-122.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [8]
RP IDENTIFICATION IN A COMPLEX WITH XPO7; ARHGAP1; EIF4A1; VPS26A; VPS29
RP AND VPS35.
RX PubMed=15282546; DOI=10.1038/sj.emboj.7600338;
RA Mingot J.-M., Bohnsack M.T., Jaekle U., Goerlich D.;
RT "Exportin 7 defines a novel general nuclear export pathway.";
RL EMBO J. 23:3227-3236(2004).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [10]
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 [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-5 AND SER-248, 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 [15]
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 [16]
RP INTERACTION WITH COPS6 AND RFWD2.
RX PubMed=21625211; DOI=10.1038/onc.2011.192;
RA Choi H.H., Gully C., Su C.H., Velazquez-Torres G., Chou P.C.,
RA Tseng C., Zhao R., Phan L., Shaiken T., Chen J., Yeung S.C., Lee M.H.;
RT "COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3
RT ubiquitin ligase for 14-3-3sigma.";
RL Oncogene 30:4791-4801(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH PHOSPHOSERINE
RP PEPTIDE.
RX PubMed=15731107; DOI=10.1074/jbc.M500982200;
RA Wilker E.W., Grant R.A., Artim S.C., Yaffe M.B.;
RT "A structural basis for 14-3-3sigma functional specificity.";
RL J. Biol. Chem. 280:18891-18898(2005).
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. When
CC bound to KRT17, regulates protein synthesis and epithelial cell
CC growth by stimulating Akt/mTOR pathway (By similarity).
CC -!- FUNCTION: p53-regulated inhibitor of G2/M progression.
CC -!- SUBUNIT: Homodimer. Interacts with KRT17 and SAMSN1 (By
CC similarity). Found in a complex with XPO7, EIF4A1, ARHGAP1,
CC VPS26A, VPS29, VPS35 and SFN. Interacts with GAB2. Interacts with
CC SRPK2. Interacts with COPS6. Interacts with RFWD2; this
CC interaction leads to proteasomal degradation.
CC -!- INTERACTION:
CC P00519:ABL1; NbExp=2; IntAct=EBI-476295, EBI-375543;
CC Q96IF1:AJUBA; NbExp=2; IntAct=EBI-476295, EBI-949782;
CC Q92934:BAD; NbExp=4; IntAct=EBI-476295, EBI-700771;
CC Q7L5N1:COPS6; NbExp=7; IntAct=EBI-476295, EBI-486838;
CC Q9UJM3:ERRFI1; NbExp=3; IntAct=EBI-476295, EBI-2941912;
CC O60269:GPRIN2; NbExp=2; IntAct=EBI-476295, EBI-740397;
CC P56524:HDAC4; NbExp=4; IntAct=EBI-476295, EBI-308629;
CC Q9UQL6:HDAC5; NbExp=3; IntAct=EBI-476295, EBI-715576;
CC Q8WUI4:HDAC7; NbExp=3; IntAct=EBI-476295, EBI-1048378;
CC Q14103-4:HNRNPD; NbExp=7; IntAct=EBI-476295, EBI-432545;
CC P27448:MARK3; NbExp=2; IntAct=EBI-476295, EBI-707595;
CC O00444:PLK4; NbExp=2; IntAct=EBI-476295, EBI-746202;
CC P04049:RAF1; NbExp=2; IntAct=EBI-476295, EBI-365996;
CC Q8NFH8-2:REPS2; NbExp=2; IntAct=EBI-476295, EBI-8029141;
CC Q8NHY2:RFWD2; NbExp=6; IntAct=EBI-476295, EBI-1176214;
CC P04637:TP53; NbExp=4; IntAct=EBI-476295, EBI-366083;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-476295, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus (By similarity).
CC Secreted. Note=May be secreted by a non-classical secretory
CC pathway.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P31947-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P31947-2; Sequence=VSP_021768;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Present mainly in tissues enriched in
CC stratified squamous keratinizing epithelium.
CC -!- SIMILARITY: Belongs to the 14-3-3 family.
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DR EMBL; M93010; AAA59546.1; -; mRNA.
DR EMBL; X57348; CAA40623.1; -; mRNA.
DR EMBL; AF029081; AAC52029.1; -; Genomic_DNA.
DR EMBL; AF029082; AAC52030.1; -; mRNA.
DR EMBL; CR541905; CAG46703.1; -; mRNA.
DR EMBL; CR541926; CAG46724.1; -; mRNA.
DR EMBL; AL034380; CAB92118.1; -; Genomic_DNA.
DR EMBL; BC000329; AAH00329.1; -; mRNA.
DR EMBL; BC000995; AAH00995.1; -; mRNA.
DR EMBL; BC001550; AAH01550.1; -; mRNA.
DR EMBL; BC002995; AAH02995.1; -; mRNA.
DR EMBL; BC023552; AAH23552.1; -; mRNA.
DR PIR; S34753; S34753.
DR PIR; S38956; S38956.
DR RefSeq; NP_006133.1; NM_006142.3.
DR UniGene; Hs.523718; -.
DR PDB; 1YWT; X-ray; 2.40 A; A/B=1-248.
DR PDB; 1YZ5; X-ray; 2.80 A; A/B=1-248.
DR PDB; 3IQJ; X-ray; 1.15 A; A=1-231.
DR PDB; 3IQU; X-ray; 1.05 A; A=1-231.
DR PDB; 3IQV; X-ray; 1.20 A; A=1-231.
DR PDB; 3LW1; X-ray; 1.28 A; A=1-248.
DR PDB; 3MHR; X-ray; 1.15 A; A=1-231.
DR PDB; 3O8I; X-ray; 2.00 A; A=1-231.
DR PDB; 3P1N; X-ray; 1.40 A; A=1-231.
DR PDB; 3P1O; X-ray; 1.90 A; A=1-231.
DR PDB; 3P1P; X-ray; 1.95 A; A=1-231.
DR PDB; 3P1Q; X-ray; 1.70 A; A=1-231.
DR PDB; 3P1R; X-ray; 1.70 A; A=1-231.
DR PDB; 3P1S; X-ray; 1.65 A; A=1-231.
DR PDB; 3SMK; X-ray; 2.10 A; A=1-231.
DR PDB; 3SML; X-ray; 1.90 A; A=1-231.
DR PDB; 3SMM; X-ray; 2.00 A; A=1-231.
DR PDB; 3SMN; X-ray; 2.00 A; A=1-231.
DR PDB; 3SMO; X-ray; 1.80 A; A=1-231.
DR PDB; 3SPR; X-ray; 1.99 A; A=1-231.
DR PDB; 3T0L; X-ray; 1.60 A; A=1-231.
DR PDB; 3T0M; X-ray; 1.62 A; A=1-231.
DR PDB; 3U9X; X-ray; 1.80 A; A=1-231.
DR PDB; 3UX0; X-ray; 1.75 A; A=1-231.
DR PDB; 4DAT; X-ray; 1.40 A; A=1-231.
DR PDB; 4DAU; X-ray; 2.00 A; A=1-231.
DR PDB; 4DHM; X-ray; 1.70 A; A=1-231.
DR PDB; 4DHN; X-ray; 1.80 A; A=1-231.
DR PDB; 4DHO; X-ray; 1.70 A; A=1-231.
DR PDB; 4DHP; X-ray; 1.75 A; A=1-231.
DR PDB; 4DHQ; X-ray; 1.75 A; A=1-231.
DR PDB; 4DHR; X-ray; 1.40 A; A=1-231.
DR PDB; 4DHS; X-ray; 1.74 A; A=1-231.
DR PDB; 4DHT; X-ray; 1.80 A; A=1-231.
DR PDB; 4DHU; X-ray; 1.67 A; A=1-231.
DR PDB; 4FR3; X-ray; 1.90 A; A=1-231.
DR PDB; 4HQW; X-ray; 2.35 A; A=1-231.
DR PDB; 4HRU; X-ray; 3.15 A; A=1-231.
DR PDB; 4IEA; X-ray; 1.70 A; A=1-231.
DR PDB; 4JC3; X-ray; 2.05 A; A=1-231.
DR PDB; 4JDD; X-ray; 2.10 A; A=1-231.
DR PDBsum; 1YWT; -.
DR PDBsum; 1YZ5; -.
DR PDBsum; 3IQJ; -.
DR PDBsum; 3IQU; -.
DR PDBsum; 3IQV; -.
DR PDBsum; 3LW1; -.
DR PDBsum; 3MHR; -.
DR PDBsum; 3O8I; -.
DR PDBsum; 3P1N; -.
DR PDBsum; 3P1O; -.
DR PDBsum; 3P1P; -.
DR PDBsum; 3P1Q; -.
DR PDBsum; 3P1R; -.
DR PDBsum; 3P1S; -.
DR PDBsum; 3SMK; -.
DR PDBsum; 3SML; -.
DR PDBsum; 3SMM; -.
DR PDBsum; 3SMN; -.
DR PDBsum; 3SMO; -.
DR PDBsum; 3SPR; -.
DR PDBsum; 3T0L; -.
DR PDBsum; 3T0M; -.
DR PDBsum; 3U9X; -.
DR PDBsum; 3UX0; -.
DR PDBsum; 4DAT; -.
DR PDBsum; 4DAU; -.
DR PDBsum; 4DHM; -.
DR PDBsum; 4DHN; -.
DR PDBsum; 4DHO; -.
DR PDBsum; 4DHP; -.
DR PDBsum; 4DHQ; -.
DR PDBsum; 4DHR; -.
DR PDBsum; 4DHS; -.
DR PDBsum; 4DHT; -.
DR PDBsum; 4DHU; -.
DR PDBsum; 4FR3; -.
DR PDBsum; 4HQW; -.
DR PDBsum; 4HRU; -.
DR PDBsum; 4IEA; -.
DR PDBsum; 4JC3; -.
DR PDBsum; 4JDD; -.
DR ProteinModelPortal; P31947; -.
DR SMR; P31947; 1-231.
DR DIP; DIP-29861N; -.
DR IntAct; P31947; 150.
DR MINT; MINT-108060; -.
DR STRING; 9606.ENSP00000340989; -.
DR BindingDB; P31947; -.
DR ChEMBL; CHEMBL1909482; -.
DR PhosphoSite; P31947; -.
DR DMDM; 398953; -.
DR OGP; P31947; -.
DR SWISS-2DPAGE; P31947; -.
DR PaxDb; P31947; -.
DR PeptideAtlas; P31947; -.
DR PRIDE; P31947; -.
DR DNASU; 2810; -.
DR Ensembl; ENST00000339276; ENSP00000340989; ENSG00000175793.
DR GeneID; 2810; -.
DR KEGG; hsa:2810; -.
DR UCSC; uc001bnc.1; human.
DR CTD; 2810; -.
DR GeneCards; GC01P027189; -.
DR HGNC; HGNC:10773; SFN.
DR HPA; CAB006268; -.
DR HPA; CAB040552; -.
DR HPA; HPA011105; -.
DR MIM; 601290; gene.
DR neXtProt; NX_P31947; -.
DR PharmGKB; PA177; -.
DR eggNOG; COG5040; -.
DR HOGENOM; HOG000240379; -.
DR HOVERGEN; HBG050423; -.
DR InParanoid; P31947; -.
DR KO; K06644; -.
DR OMA; EQKGNEE; -.
DR OrthoDB; EOG7HHWT3; -.
DR PhylomeDB; P31947; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; P31947; -.
DR EvolutionaryTrace; P31947; -.
DR GeneWiki; Stratifin; -.
DR GenomeRNAi; 2810; -.
DR NextBio; 11071; -.
DR PRO; PR:P31947; -.
DR Bgee; P31947; -.
DR CleanEx; HS_SFN; -.
DR Genevestigator; P31947; -.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0008426; F:protein kinase C inhibitor activity; TAS:ProtInc.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:HGNC.
DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR GO; GO:0043616; P:keratinocyte proliferation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:HGNC.
DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IEA:Ensembl.
DR GO; GO:1900740; P:positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Ensembl.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IDA:HGNC.
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; Alternative splicing; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted.
FT CHAIN 1 248 14-3-3 protein sigma.
FT /FTId=PRO_0000058643.
FT SITE 56 56 Interaction with phosphoserine on
FT interacting protein.
FT SITE 129 129 Interaction with phosphoserine on
FT interacting protein.
FT MOD_RES 5 5 Phosphoserine.
FT MOD_RES 248 248 Phosphoserine.
FT VAR_SEQ 85 116 Missing (in isoform 2).
FT /FTId=VSP_021768.
FT VARIANT 155 155 M -> I (in dbSNP:rs11542705).
FT /FTId=VAR_048095.
FT CONFLICT 77 77 K -> M (in Ref. 4; CAG46703).
FT CONFLICT 120 120 Y -> H (in Ref. 2; AAA59546).
FT CONFLICT 242 242 A -> V (in Ref. 2; AAA59546).
FT HELIX 3 15
FT HELIX 19 31
FT HELIX 38 69
FT HELIX 80 104
FT HELIX 107 110
FT HELIX 114 134
FT STRAND 137 139
FT HELIX 140 161
FT HELIX 167 182
FT HELIX 187 204
FT HELIX 205 207
FT HELIX 210 230
SQ SEQUENCE 248 AA; 27774 MW; 7F4B44E3AA59ECE6 CRC64;
MERASLIQKA KLAEQAERYE DMAAFMKGAV EKGEELSCEE RNLLSVAYKN VVGGQRAAWR
VLSSIEQKSN EEGSEEKGPE VREYREKVET ELQGVCDTVL GLLDSHLIKE AGDAESRVFY
LKMKGDYYRY LAEVATGDDK KRIIDSARSA YQEAMDISKK EMPPTNPIRL GLALNFSVFH
YEIANSPEEA ISLAKTTFDE AMADLHTLSE DSYKDSTLIM QLLRDNLTLW TADNAGEEGG
EAPQEPQS
//
ID 1433S_HUMAN Reviewed; 248 AA.
AC P31947; Q6FH30; Q6FH51; Q96DH0;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1993, sequence version 1.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=14-3-3 protein sigma;
DE AltName: Full=Epithelial cell marker protein 1;
DE AltName: Full=Stratifin;
GN Name=SFN; Synonyms=HME1;
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=Epithelium;
RX PubMed=1390337;
RA Prasad G.L., Valverius E.M., McDuffie E., Cooper H.L.;
RT "Complementary DNA cloning of a novel epithelial cell marker protein,
RT HME1, that may be down-regulated in neoplastic mammary cells.";
RL Cell Growth Differ. 3:507-513(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 19-25;
RP 42-49; 118-122; 130-139; 149-159; 161-181; 196-199; 225-229 AND
RP 231-239.
RC TISSUE=Keratinocyte;
RX PubMed=8515476; DOI=10.1006/jmbi.1993.1346;
RA Leffers H., Madsen P., Rasmussen H.H., Honore B., Andersen A.H.,
RA Walbum E., Vandekerckhove J., Celis J.E.;
RT "Molecular cloning and expression of the transformation sensitive
RT epithelial marker stratifin. A member of a protein family that has
RT been involved in the protein kinase C signalling pathway.";
RL J. Mol. Biol. 231:982-998(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=9659898; DOI=10.1016/S1097-2765(00)80002-7;
RA Hermeking H., Lengauer C., Polyak K., He T.-C., Zhang L.,
RA Thiagalingam S., Kinzler K.W., Vogelstein B.;
RT "14-3-3 sigma is a p53-regulated inhibitor of G2/M progression.";
RL Mol. Cell 1:3-11(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cervix, Lung, and 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 [7]
RP PROTEIN SEQUENCE OF 42-49 AND 118-122.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [8]
RP IDENTIFICATION IN A COMPLEX WITH XPO7; ARHGAP1; EIF4A1; VPS26A; VPS29
RP AND VPS35.
RX PubMed=15282546; DOI=10.1038/sj.emboj.7600338;
RA Mingot J.-M., Bohnsack M.T., Jaekle U., Goerlich D.;
RT "Exportin 7 defines a novel general nuclear export pathway.";
RL EMBO J. 23:3227-3236(2004).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [10]
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 [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-5 AND SER-248, 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 [15]
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 [16]
RP INTERACTION WITH COPS6 AND RFWD2.
RX PubMed=21625211; DOI=10.1038/onc.2011.192;
RA Choi H.H., Gully C., Su C.H., Velazquez-Torres G., Chou P.C.,
RA Tseng C., Zhao R., Phan L., Shaiken T., Chen J., Yeung S.C., Lee M.H.;
RT "COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3
RT ubiquitin ligase for 14-3-3sigma.";
RL Oncogene 30:4791-4801(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH PHOSPHOSERINE
RP PEPTIDE.
RX PubMed=15731107; DOI=10.1074/jbc.M500982200;
RA Wilker E.W., Grant R.A., Artim S.C., Yaffe M.B.;
RT "A structural basis for 14-3-3sigma functional specificity.";
RL J. Biol. Chem. 280:18891-18898(2005).
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. When
CC bound to KRT17, regulates protein synthesis and epithelial cell
CC growth by stimulating Akt/mTOR pathway (By similarity).
CC -!- FUNCTION: p53-regulated inhibitor of G2/M progression.
CC -!- SUBUNIT: Homodimer. Interacts with KRT17 and SAMSN1 (By
CC similarity). Found in a complex with XPO7, EIF4A1, ARHGAP1,
CC VPS26A, VPS29, VPS35 and SFN. Interacts with GAB2. Interacts with
CC SRPK2. Interacts with COPS6. Interacts with RFWD2; this
CC interaction leads to proteasomal degradation.
CC -!- INTERACTION:
CC P00519:ABL1; NbExp=2; IntAct=EBI-476295, EBI-375543;
CC Q96IF1:AJUBA; NbExp=2; IntAct=EBI-476295, EBI-949782;
CC Q92934:BAD; NbExp=4; IntAct=EBI-476295, EBI-700771;
CC Q7L5N1:COPS6; NbExp=7; IntAct=EBI-476295, EBI-486838;
CC Q9UJM3:ERRFI1; NbExp=3; IntAct=EBI-476295, EBI-2941912;
CC O60269:GPRIN2; NbExp=2; IntAct=EBI-476295, EBI-740397;
CC P56524:HDAC4; NbExp=4; IntAct=EBI-476295, EBI-308629;
CC Q9UQL6:HDAC5; NbExp=3; IntAct=EBI-476295, EBI-715576;
CC Q8WUI4:HDAC7; NbExp=3; IntAct=EBI-476295, EBI-1048378;
CC Q14103-4:HNRNPD; NbExp=7; IntAct=EBI-476295, EBI-432545;
CC P27448:MARK3; NbExp=2; IntAct=EBI-476295, EBI-707595;
CC O00444:PLK4; NbExp=2; IntAct=EBI-476295, EBI-746202;
CC P04049:RAF1; NbExp=2; IntAct=EBI-476295, EBI-365996;
CC Q8NFH8-2:REPS2; NbExp=2; IntAct=EBI-476295, EBI-8029141;
CC Q8NHY2:RFWD2; NbExp=6; IntAct=EBI-476295, EBI-1176214;
CC P04637:TP53; NbExp=4; IntAct=EBI-476295, EBI-366083;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-476295, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus (By similarity).
CC Secreted. Note=May be secreted by a non-classical secretory
CC pathway.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P31947-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P31947-2; Sequence=VSP_021768;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Present mainly in tissues enriched in
CC stratified squamous keratinizing epithelium.
CC -!- SIMILARITY: Belongs to the 14-3-3 family.
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DR EMBL; M93010; AAA59546.1; -; mRNA.
DR EMBL; X57348; CAA40623.1; -; mRNA.
DR EMBL; AF029081; AAC52029.1; -; Genomic_DNA.
DR EMBL; AF029082; AAC52030.1; -; mRNA.
DR EMBL; CR541905; CAG46703.1; -; mRNA.
DR EMBL; CR541926; CAG46724.1; -; mRNA.
DR EMBL; AL034380; CAB92118.1; -; Genomic_DNA.
DR EMBL; BC000329; AAH00329.1; -; mRNA.
DR EMBL; BC000995; AAH00995.1; -; mRNA.
DR EMBL; BC001550; AAH01550.1; -; mRNA.
DR EMBL; BC002995; AAH02995.1; -; mRNA.
DR EMBL; BC023552; AAH23552.1; -; mRNA.
DR PIR; S34753; S34753.
DR PIR; S38956; S38956.
DR RefSeq; NP_006133.1; NM_006142.3.
DR UniGene; Hs.523718; -.
DR PDB; 1YWT; X-ray; 2.40 A; A/B=1-248.
DR PDB; 1YZ5; X-ray; 2.80 A; A/B=1-248.
DR PDB; 3IQJ; X-ray; 1.15 A; A=1-231.
DR PDB; 3IQU; X-ray; 1.05 A; A=1-231.
DR PDB; 3IQV; X-ray; 1.20 A; A=1-231.
DR PDB; 3LW1; X-ray; 1.28 A; A=1-248.
DR PDB; 3MHR; X-ray; 1.15 A; A=1-231.
DR PDB; 3O8I; X-ray; 2.00 A; A=1-231.
DR PDB; 3P1N; X-ray; 1.40 A; A=1-231.
DR PDB; 3P1O; X-ray; 1.90 A; A=1-231.
DR PDB; 3P1P; X-ray; 1.95 A; A=1-231.
DR PDB; 3P1Q; X-ray; 1.70 A; A=1-231.
DR PDB; 3P1R; X-ray; 1.70 A; A=1-231.
DR PDB; 3P1S; X-ray; 1.65 A; A=1-231.
DR PDB; 3SMK; X-ray; 2.10 A; A=1-231.
DR PDB; 3SML; X-ray; 1.90 A; A=1-231.
DR PDB; 3SMM; X-ray; 2.00 A; A=1-231.
DR PDB; 3SMN; X-ray; 2.00 A; A=1-231.
DR PDB; 3SMO; X-ray; 1.80 A; A=1-231.
DR PDB; 3SPR; X-ray; 1.99 A; A=1-231.
DR PDB; 3T0L; X-ray; 1.60 A; A=1-231.
DR PDB; 3T0M; X-ray; 1.62 A; A=1-231.
DR PDB; 3U9X; X-ray; 1.80 A; A=1-231.
DR PDB; 3UX0; X-ray; 1.75 A; A=1-231.
DR PDB; 4DAT; X-ray; 1.40 A; A=1-231.
DR PDB; 4DAU; X-ray; 2.00 A; A=1-231.
DR PDB; 4DHM; X-ray; 1.70 A; A=1-231.
DR PDB; 4DHN; X-ray; 1.80 A; A=1-231.
DR PDB; 4DHO; X-ray; 1.70 A; A=1-231.
DR PDB; 4DHP; X-ray; 1.75 A; A=1-231.
DR PDB; 4DHQ; X-ray; 1.75 A; A=1-231.
DR PDB; 4DHR; X-ray; 1.40 A; A=1-231.
DR PDB; 4DHS; X-ray; 1.74 A; A=1-231.
DR PDB; 4DHT; X-ray; 1.80 A; A=1-231.
DR PDB; 4DHU; X-ray; 1.67 A; A=1-231.
DR PDB; 4FR3; X-ray; 1.90 A; A=1-231.
DR PDB; 4HQW; X-ray; 2.35 A; A=1-231.
DR PDB; 4HRU; X-ray; 3.15 A; A=1-231.
DR PDB; 4IEA; X-ray; 1.70 A; A=1-231.
DR PDB; 4JC3; X-ray; 2.05 A; A=1-231.
DR PDB; 4JDD; X-ray; 2.10 A; A=1-231.
DR PDBsum; 1YWT; -.
DR PDBsum; 1YZ5; -.
DR PDBsum; 3IQJ; -.
DR PDBsum; 3IQU; -.
DR PDBsum; 3IQV; -.
DR PDBsum; 3LW1; -.
DR PDBsum; 3MHR; -.
DR PDBsum; 3O8I; -.
DR PDBsum; 3P1N; -.
DR PDBsum; 3P1O; -.
DR PDBsum; 3P1P; -.
DR PDBsum; 3P1Q; -.
DR PDBsum; 3P1R; -.
DR PDBsum; 3P1S; -.
DR PDBsum; 3SMK; -.
DR PDBsum; 3SML; -.
DR PDBsum; 3SMM; -.
DR PDBsum; 3SMN; -.
DR PDBsum; 3SMO; -.
DR PDBsum; 3SPR; -.
DR PDBsum; 3T0L; -.
DR PDBsum; 3T0M; -.
DR PDBsum; 3U9X; -.
DR PDBsum; 3UX0; -.
DR PDBsum; 4DAT; -.
DR PDBsum; 4DAU; -.
DR PDBsum; 4DHM; -.
DR PDBsum; 4DHN; -.
DR PDBsum; 4DHO; -.
DR PDBsum; 4DHP; -.
DR PDBsum; 4DHQ; -.
DR PDBsum; 4DHR; -.
DR PDBsum; 4DHS; -.
DR PDBsum; 4DHT; -.
DR PDBsum; 4DHU; -.
DR PDBsum; 4FR3; -.
DR PDBsum; 4HQW; -.
DR PDBsum; 4HRU; -.
DR PDBsum; 4IEA; -.
DR PDBsum; 4JC3; -.
DR PDBsum; 4JDD; -.
DR ProteinModelPortal; P31947; -.
DR SMR; P31947; 1-231.
DR DIP; DIP-29861N; -.
DR IntAct; P31947; 150.
DR MINT; MINT-108060; -.
DR STRING; 9606.ENSP00000340989; -.
DR BindingDB; P31947; -.
DR ChEMBL; CHEMBL1909482; -.
DR PhosphoSite; P31947; -.
DR DMDM; 398953; -.
DR OGP; P31947; -.
DR SWISS-2DPAGE; P31947; -.
DR PaxDb; P31947; -.
DR PeptideAtlas; P31947; -.
DR PRIDE; P31947; -.
DR DNASU; 2810; -.
DR Ensembl; ENST00000339276; ENSP00000340989; ENSG00000175793.
DR GeneID; 2810; -.
DR KEGG; hsa:2810; -.
DR UCSC; uc001bnc.1; human.
DR CTD; 2810; -.
DR GeneCards; GC01P027189; -.
DR HGNC; HGNC:10773; SFN.
DR HPA; CAB006268; -.
DR HPA; CAB040552; -.
DR HPA; HPA011105; -.
DR MIM; 601290; gene.
DR neXtProt; NX_P31947; -.
DR PharmGKB; PA177; -.
DR eggNOG; COG5040; -.
DR HOGENOM; HOG000240379; -.
DR HOVERGEN; HBG050423; -.
DR InParanoid; P31947; -.
DR KO; K06644; -.
DR OMA; EQKGNEE; -.
DR OrthoDB; EOG7HHWT3; -.
DR PhylomeDB; P31947; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; P31947; -.
DR EvolutionaryTrace; P31947; -.
DR GeneWiki; Stratifin; -.
DR GenomeRNAi; 2810; -.
DR NextBio; 11071; -.
DR PRO; PR:P31947; -.
DR Bgee; P31947; -.
DR CleanEx; HS_SFN; -.
DR Genevestigator; P31947; -.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0008426; F:protein kinase C inhibitor activity; TAS:ProtInc.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:HGNC.
DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR GO; GO:0043616; P:keratinocyte proliferation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:HGNC.
DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IEA:Ensembl.
DR GO; GO:1900740; P:positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Ensembl.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IDA:HGNC.
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; Alternative splicing; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted.
FT CHAIN 1 248 14-3-3 protein sigma.
FT /FTId=PRO_0000058643.
FT SITE 56 56 Interaction with phosphoserine on
FT interacting protein.
FT SITE 129 129 Interaction with phosphoserine on
FT interacting protein.
FT MOD_RES 5 5 Phosphoserine.
FT MOD_RES 248 248 Phosphoserine.
FT VAR_SEQ 85 116 Missing (in isoform 2).
FT /FTId=VSP_021768.
FT VARIANT 155 155 M -> I (in dbSNP:rs11542705).
FT /FTId=VAR_048095.
FT CONFLICT 77 77 K -> M (in Ref. 4; CAG46703).
FT CONFLICT 120 120 Y -> H (in Ref. 2; AAA59546).
FT CONFLICT 242 242 A -> V (in Ref. 2; AAA59546).
FT HELIX 3 15
FT HELIX 19 31
FT HELIX 38 69
FT HELIX 80 104
FT HELIX 107 110
FT HELIX 114 134
FT STRAND 137 139
FT HELIX 140 161
FT HELIX 167 182
FT HELIX 187 204
FT HELIX 205 207
FT HELIX 210 230
SQ SEQUENCE 248 AA; 27774 MW; 7F4B44E3AA59ECE6 CRC64;
MERASLIQKA KLAEQAERYE DMAAFMKGAV EKGEELSCEE RNLLSVAYKN VVGGQRAAWR
VLSSIEQKSN EEGSEEKGPE VREYREKVET ELQGVCDTVL GLLDSHLIKE AGDAESRVFY
LKMKGDYYRY LAEVATGDDK KRIIDSARSA YQEAMDISKK EMPPTNPIRL GLALNFSVFH
YEIANSPEEA ISLAKTTFDE AMADLHTLSE DSYKDSTLIM QLLRDNLTLW TADNAGEEGG
EAPQEPQS
//
MIM
601290
*RECORD*
*FIELD* NO
601290
*FIELD* TI
*601290 STRATIFIN; SFN
;;14-3-3-SIGMA
*FIELD* TX
DESCRIPTION
SFN, or 14-3-3-sigma, is a regulator of mitotic translation that
read moreinteracts with a variety of translation and initiation factors (Wilker
et al., 2007).
CLONING
Leffers et al. (1993) obtained peptide sequence and subsequently cloned
a T-cell cDNA of the 14-3-3 family (see 113508) of conserved proteins.
The protein, called stratifin, was shown to be diffusely distributed in
the cytoplasm and was present in cultured epithelial cells. It was most
abundant in tissues enriched in stratified keratinizing epithelium.
MAPPING
Hermeking et al. (1997) mapped the SFN gene to chromosome 1p35 using
fluorescence in situ hybridization.
GENE FUNCTION
Through a quantitative analysis of gene expression patterns in
colorectal cancer cell lines, Hermeking et al. (1997) discovered that
14-3-3-sigma, or stratifin, is strongly induced by gamma irradiation and
other DNA-damaging agents. The induction of 14-3-3-sigma is mediated by
a p53 (191170)-responsive element located 1.8 kb upstream of its
transcription start site. Exogenous introduction of 14-3-3-sigma into
cycling cells results in a G2 arrest. As the fission yeast 14-3-3
homologs rad24 and rad25 mediate similar checkpoint effects, Hermeking
et al. (1997) concluded that the results document a molecular mechanism
for G2/M control that is conserved throughout eukaryotic evolution and
regulated in human cells by p53.
Chan et al. (1999) described an improved approach to the generation of
human somatic cell knockouts, which they used to generate human
colorectal cancer cells in which both 14-3-3-sigma alleles were
inactivated. After DNA damage, these cells initially arrested in the G2
phase of the cell cycle, but unlike cells containing 14-3-3-sigma, the
14-3-3-sigma -/- cells were unable to maintain cell cycle arrest. The
14-3-3-sigma -/- cells died (mitotic catastrophe) as they entered
mitosis. This process was associated with a failure of the
14-3-3-sigma-deficient cells to sequester the proteins (cyclin B,
123836; CDC2, 116940) that initiate mitosis and prevent them from
entering the nucleus. Chan et al. (1999) concluded that these results
indicated a mechanism for maintaining the G2 checkpoint and preventing
mitotic death.
Expression of 14-3-3-sigma is induced in response to DNA damage, and
causes cells to arrest in G2. By SAGE, Ferguson et al. (2000) identified
sigma as a gene whose expression is 7-fold lower in breast carcinoma
cells than in normal breast epithelium. Although genetic alterations at
the SFN locus such as loss of heterozygosity were rare and no mutations
were detected, the authors found that hypermethylation of CpG islands in
the SFN gene could be detected in 91% of breast tumors and was
associated with lack of gene expression. Treatment of
sigma-nonexpressing breast cancer cell lines with the drug
5-aza-2-prime-deoxycytidine resulted in demethylation of the gene and
synthesis of sigma mRNA. Breast cancer cells lacking sigma expression
showed an increased number of chromosomal breaks and gaps when exposed
to gamma-irradiation. Ferguson et al. (2000) thought it possible that
loss of sigma expression contributes to malignant transformation by
impairing the G2 cell cycle checkpoint function, thus allowing an
accumulation of genetic defects. They suggested that hypermethylation
and loss of sigma expression were the most consistent molecular
alterations identified in breast cancer.
Urano et al. (2002) demonstrated that EFP (600453) is a
RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of
14-3-3-sigma, a negative cell cycle regulator that causes G2 arrest.
Urano et al. (2002) demonstrated that tumor growth of breast cancer MCF7
cells implanted in female athymic mice is reduced by treatment with
antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in
ovariectomized athymic mice generated tumors in the absence of estrogen.
Loss of Efp function in mouse embryonic fibroblasts resulted in an
accumulation of 14-3-3-sigma, which was responsible for reduced cell
growth. Urano et al. (2002) concluded that their data provide an insight
into the cell cycle machinery and tumorigenesis of breast cancer by
identifying 14-3-3-sigma as a target for proteolysis by EFP, leading to
cell proliferation.
Wilker et al. (2007) reported a previously unknown function for
14-3-3-sigma as a regulator of mitotic translation through its direct
mitosis-specific binding to a variety of translation/initiation factors,
including eukaryotic initiation factor 4B (EIF4B; 603928) in a
stoichiometric manner. Cells lacking 14-3-3-sigma, in marked contrast to
normal cells, cannot suppress cap-dependent translation and do not
stimulate cap-independent translation during and immediately after
mitosis. This defective switch in the mechanism of translation results
in reduced mitotic-specific expression of the endogenous internal
ribosomal entry site (IRES)-dependent form of the cyclin-dependent
kinase CDK11 (p58 PITSLRE; 176873), leading to impaired cytokinesis,
loss of Polo-like kinase-1 (602098) at the midbody, and the accumulation
of binucleate cells. The aberrant mitotic phenotype of
14-3-3-sigma-depleted cells can be rescued by forced expression of CDK11
or by extinguishing cap-dependent translation and increasing
cap-independent translation during mitosis by using rapamycin. Wilker et
al. (2007) concluded that their findings showed how aberrant mitotic
translation in the absence of 14-3-3-sigma impairs mitotic exit to
generate binucleate cells and provides a potential explanation of how
14-3-3-sigma-deficient cells may progress on the path to aneuploidy and
tumorigenesis.
A large proportion of aggressive squamous cell carcinomas in humans and
mice express markedly reduced IKKA (CHUK; 600664), and somatic mutations
in IKKA have been identified in human squamous cell carcinomas. Zhu et
al. (2007) identified 14-3-3-sigma as a downstream target of Ikka in
cell cycle regulation in response to DNA damage and found that the
14-3-3-sigma locus was hypermethylated in Ikka -/- mouse keratinocytes,
but not in wildtype keratinocytes. Trimethylated histone H3-lys9 (see
602810) associated with Suv39h1 (300254) and Dnmt3a (602769) in the
methylated 14-3-3-sigma locus. Reintroduction of Ikka restored
14-3-3-sigma expression by associating with H3 and preventing access of
Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3-sigma. Zhu
et al. (2007) concluded that IKKA protects the 14-3-3-sigma locus from
hypermethylation, which serves as a mechanism of maintaining genomic
stability in keratinocytes.
Choi et al. (2011) showed that the ubiquitin ligase COP1 (RFWD2; 608067)
targeted 14-3-3-sigma for ubiquitin-mediated degradation in human cell
lines. The COP9 signalosome subunit COPS6 (614729) stabilized COP1 by
reducing COP1 autoubiquitination, resulting in elevated 14-3-3-sigma
ubiquitination and degradation.
BIOCHEMICAL FEATURES
The 14-3-3 family of proteins mediates signal transduction by binding to
phosphoserine-containing proteins. Using phosphoserine-oriented peptide
libraries to probe all mammalian and yeast 14-3-3s, Yaffe et al. (1997)
identified 2 different binding motifs, RSXpSXP and RXY/FXpSXP, present
in nearly all known 14-3-3 binding proteins. The crystal structure of
YWHAZ (601288) complexed with the phosphoserine motif in polyoma
middle-T was determined to 2.6-angstrom resolution. The authors showed
that the 14-3-3 dimer binds tightly to single molecules containing
tandem repeats of phosphoserine motifs, implicating bidentate
association as a signaling mechanism with molecules such as Raf, BAD
(603167), and Cbl.
ANIMAL MODEL
Stratifin is highly expressed in differentiating epidermis and mediates
cell cycle arrest. To extend understanding of skin development, Herron
et al. (2005) set out to identify the causal mutation in 'repeated
epilation' (Er) mutant mice. The heterozygous mutant (Er/+) mouse was
originally identified in the offspring of a male exposed to gamma
radiation; the mutant had a disheveled appearance at 3 weeks of age.
Older heterozygous mice had an increased incidence of papillomas and
squamous cell carcinomas. Linkage studies localized the Er gene to mouse
chromosome 4 in an 820-kb region containing 22 genes. Among these genes,
Sfn was considered a good candidate for underlying the Er mutation
because it has a role in keratinocyte differentiation and because Sfn
expression is abnormal in epithelial cancers. Sequencing of the Sfn open
reading frame in genomic DNA from homozygous Er/Er and wildtype mice
detected a single T insertion at basepair 622 in homozygous mutant mice.
This frameshift mutation at amino acid 207 truncates the C terminus of
the protein encoded by the Er allele, eliminating residues required for
ligand interaction and the nuclear export sequence.
By gene expression analysis of skin and embryonic fibroblasts from
wildtype and Er mice, Li et al. (2005) identified a 1-bp insertion
(642insT) in the Sfn gene that results in the Er phenotype. The
insertion causes a frameshift leading to a truncated protein lacking 40
amino acids at the C terminus. Li et al. (2005) noted that Er/+ adult
mice showed repeated hair loss, whereas Er/Er mutant mice died at birth
due to respiratory distress and skin defects, with hyperplastic
epidermis, failure of keratinocyte differentiation, and abnormal
craniofacial development. Ectopic overexpression of Sfn in Er/Er
keratinocytes rescued the defects of keratinocyte differentiation.
*FIELD* RF
1. Chan, T. A.; Hermeking, H.; Langauer, C.; Kinzler, K. W.; Vogelstein,
B.: 14-3-3-sigma is required to prevent mitotic catastrophe after
DNA damage. Nature 401: 616-620, 1999.
2. Choi, H. H.; Gully, C.; Su, C.-H.; Velazquez-Torres, G.; Chou,
P.-C.; Tseng, C.; Zhao, R.; Phan, L.; Shaiken, T.; Chen, J.; Yeung,
S. C.; Lee, M.-H.: COP9 signalosome subunit 6 stabilizes COP1, which
functions as an E3 ubiquitin ligase for 14-3-3-sigma. Oncogene 30:
4791-4801, 2011.
3. Ferguson, A. T.; Evron, E.; Umbricht, C. B.; Pandita, T. K.; Chan,
T. A.; Hermeking, H.; Marks, J. R.; Lambers, A. R.; Futreal, P. A.;
Stampfer, M. R.; Sukumar, S.: High frequency of hypermethylation
at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc.
Nat. Acad. Sci. 97: 6049-6054, 2000.
4. Hermeking, H.; Lengauer, C.; Polyak, K.; He, T.-C.; Zhang, L.;
Thiagalingam, S.; Kinzler, K. W.; Vogelstein, B.: 14-3-3-sigma is
a p53-regulated inhibitor of G2/M progression. Molec. Cell 1: 3-11,
1997.
5. Herron, B. J.; Liddell, R. A.; Parker, A.; Grant, S.; Kinne, J.;
Fisher, J. K.; Siracusa, L. D.: A mutation in stratifin is responsible
for the repeated epilation (Er) phenotype in mice. Nature Genet. 37:
1210-1212, 2005.
6. Leffers, H.; Madsen, P.; Rasmussen, H. H.; Honore, B.; Andersen,
A. H.; Walbum, E.; Vandekerckhove, J.; Celis, J. E.: Molecular cloning
and expression of the transformation sensitive epithelial marker stratifin:
a member of a protein family that has been involved in the protein
kinase C signalling pathway. J. Molec. Biol. 231: 982-998, 1993.
7. Li, Q.; Lu, Q.; Estepa, G.; Verma, I. M.: Identification of 14-3-3-sigma
mutation causing cutaneous abnormality in repeated-epilation mutant
mouse. Proc. Nat. Acad. Sci. 102: 15977-15982, 2005.
8. Urano, T.; Saito, T.; Tsukui, T.; Fujita, M.; Hosoi, T.; Muramatsu,
M.; Ouchi, Y.; Inoue, S.: Efp targets 14-3-3-sigma for proteolysis
and promotes breast tumour growth. Nature 417: 871-875, 2002.
9. Wilker, E. W.; van Vugt, M. A. T. M.; Artim, S. A.; Huang, P. H.;
Petersen, C. P.; Reinhardt, H. C.; Feng, Y.; Sharp, P. A.; Sonenberg,
N.; White, F. M.; Yaffe, M. B.: 14-3-3-sigma controls mitotic translation
to facilitate cytokinesis. Nature 446: 329-332, 2007.
10. Yaffe, M. B.; Rittinger, K.; Volinia, S.; Caron, P. R.; Aitken,
A.; Leffers, H.; Gamblin, S. J.; Smerdon, S. J.; Cantley, L. C.:
The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91:
961-971, 1997.
11. Zhu, F.; Xia, X.; Liu, B.; Shen, J.; Hu, Y.; Person, M.; Hu, Y.
: IKK-alpha shields 14-3-3-sigma, a G2/M cell cycle checkpoint gene,
from hypermethylation, preventing its silencing. Molec. Cell 27:
214-227, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 7/11/2012
Patricia A. Hartz - updated: 9/19/2007
Cassandra L. Kniffin - updated: 6/11/2007
Ada Hamosh - updated: 5/1/2007
Anne M. Stumpf - updated: 11/2/2005
Victor A. McKusick - updated: 11/1/2005
Ada Hamosh - updated: 7/12/2002
Victor A. McKusick - updated: 8/4/2000
Ada Hamosh - updated: 10/18/1999
Stylianos E. Antonarakis - updated: 2/20/1998
*FIELD* CD
Alan F. Scott: 6/3/1996
*FIELD* ED
mgross: 02/05/2013
mgross: 7/18/2012
terry: 7/11/2012
mgross: 9/28/2007
terry: 9/19/2007
wwang: 7/9/2007
ckniffin: 6/11/2007
alopez: 5/7/2007
terry: 5/1/2007
alopez: 11/2/2005
terry: 11/1/2005
tkritzer: 1/5/2004
alopez: 7/16/2002
terry: 7/12/2002
mcapotos: 8/10/2000
mcapotos: 8/8/2000
terry: 8/4/2000
alopez: 10/20/1999
terry: 10/18/1999
terry: 11/13/1998
alopez: 10/20/1998
dholmes: 2/20/1998
terry: 6/3/1996
mark: 6/3/1996
*RECORD*
*FIELD* NO
601290
*FIELD* TI
*601290 STRATIFIN; SFN
;;14-3-3-SIGMA
*FIELD* TX
DESCRIPTION
SFN, or 14-3-3-sigma, is a regulator of mitotic translation that
read moreinteracts with a variety of translation and initiation factors (Wilker
et al., 2007).
CLONING
Leffers et al. (1993) obtained peptide sequence and subsequently cloned
a T-cell cDNA of the 14-3-3 family (see 113508) of conserved proteins.
The protein, called stratifin, was shown to be diffusely distributed in
the cytoplasm and was present in cultured epithelial cells. It was most
abundant in tissues enriched in stratified keratinizing epithelium.
MAPPING
Hermeking et al. (1997) mapped the SFN gene to chromosome 1p35 using
fluorescence in situ hybridization.
GENE FUNCTION
Through a quantitative analysis of gene expression patterns in
colorectal cancer cell lines, Hermeking et al. (1997) discovered that
14-3-3-sigma, or stratifin, is strongly induced by gamma irradiation and
other DNA-damaging agents. The induction of 14-3-3-sigma is mediated by
a p53 (191170)-responsive element located 1.8 kb upstream of its
transcription start site. Exogenous introduction of 14-3-3-sigma into
cycling cells results in a G2 arrest. As the fission yeast 14-3-3
homologs rad24 and rad25 mediate similar checkpoint effects, Hermeking
et al. (1997) concluded that the results document a molecular mechanism
for G2/M control that is conserved throughout eukaryotic evolution and
regulated in human cells by p53.
Chan et al. (1999) described an improved approach to the generation of
human somatic cell knockouts, which they used to generate human
colorectal cancer cells in which both 14-3-3-sigma alleles were
inactivated. After DNA damage, these cells initially arrested in the G2
phase of the cell cycle, but unlike cells containing 14-3-3-sigma, the
14-3-3-sigma -/- cells were unable to maintain cell cycle arrest. The
14-3-3-sigma -/- cells died (mitotic catastrophe) as they entered
mitosis. This process was associated with a failure of the
14-3-3-sigma-deficient cells to sequester the proteins (cyclin B,
123836; CDC2, 116940) that initiate mitosis and prevent them from
entering the nucleus. Chan et al. (1999) concluded that these results
indicated a mechanism for maintaining the G2 checkpoint and preventing
mitotic death.
Expression of 14-3-3-sigma is induced in response to DNA damage, and
causes cells to arrest in G2. By SAGE, Ferguson et al. (2000) identified
sigma as a gene whose expression is 7-fold lower in breast carcinoma
cells than in normal breast epithelium. Although genetic alterations at
the SFN locus such as loss of heterozygosity were rare and no mutations
were detected, the authors found that hypermethylation of CpG islands in
the SFN gene could be detected in 91% of breast tumors and was
associated with lack of gene expression. Treatment of
sigma-nonexpressing breast cancer cell lines with the drug
5-aza-2-prime-deoxycytidine resulted in demethylation of the gene and
synthesis of sigma mRNA. Breast cancer cells lacking sigma expression
showed an increased number of chromosomal breaks and gaps when exposed
to gamma-irradiation. Ferguson et al. (2000) thought it possible that
loss of sigma expression contributes to malignant transformation by
impairing the G2 cell cycle checkpoint function, thus allowing an
accumulation of genetic defects. They suggested that hypermethylation
and loss of sigma expression were the most consistent molecular
alterations identified in breast cancer.
Urano et al. (2002) demonstrated that EFP (600453) is a
RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of
14-3-3-sigma, a negative cell cycle regulator that causes G2 arrest.
Urano et al. (2002) demonstrated that tumor growth of breast cancer MCF7
cells implanted in female athymic mice is reduced by treatment with
antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in
ovariectomized athymic mice generated tumors in the absence of estrogen.
Loss of Efp function in mouse embryonic fibroblasts resulted in an
accumulation of 14-3-3-sigma, which was responsible for reduced cell
growth. Urano et al. (2002) concluded that their data provide an insight
into the cell cycle machinery and tumorigenesis of breast cancer by
identifying 14-3-3-sigma as a target for proteolysis by EFP, leading to
cell proliferation.
Wilker et al. (2007) reported a previously unknown function for
14-3-3-sigma as a regulator of mitotic translation through its direct
mitosis-specific binding to a variety of translation/initiation factors,
including eukaryotic initiation factor 4B (EIF4B; 603928) in a
stoichiometric manner. Cells lacking 14-3-3-sigma, in marked contrast to
normal cells, cannot suppress cap-dependent translation and do not
stimulate cap-independent translation during and immediately after
mitosis. This defective switch in the mechanism of translation results
in reduced mitotic-specific expression of the endogenous internal
ribosomal entry site (IRES)-dependent form of the cyclin-dependent
kinase CDK11 (p58 PITSLRE; 176873), leading to impaired cytokinesis,
loss of Polo-like kinase-1 (602098) at the midbody, and the accumulation
of binucleate cells. The aberrant mitotic phenotype of
14-3-3-sigma-depleted cells can be rescued by forced expression of CDK11
or by extinguishing cap-dependent translation and increasing
cap-independent translation during mitosis by using rapamycin. Wilker et
al. (2007) concluded that their findings showed how aberrant mitotic
translation in the absence of 14-3-3-sigma impairs mitotic exit to
generate binucleate cells and provides a potential explanation of how
14-3-3-sigma-deficient cells may progress on the path to aneuploidy and
tumorigenesis.
A large proportion of aggressive squamous cell carcinomas in humans and
mice express markedly reduced IKKA (CHUK; 600664), and somatic mutations
in IKKA have been identified in human squamous cell carcinomas. Zhu et
al. (2007) identified 14-3-3-sigma as a downstream target of Ikka in
cell cycle regulation in response to DNA damage and found that the
14-3-3-sigma locus was hypermethylated in Ikka -/- mouse keratinocytes,
but not in wildtype keratinocytes. Trimethylated histone H3-lys9 (see
602810) associated with Suv39h1 (300254) and Dnmt3a (602769) in the
methylated 14-3-3-sigma locus. Reintroduction of Ikka restored
14-3-3-sigma expression by associating with H3 and preventing access of
Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3-sigma. Zhu
et al. (2007) concluded that IKKA protects the 14-3-3-sigma locus from
hypermethylation, which serves as a mechanism of maintaining genomic
stability in keratinocytes.
Choi et al. (2011) showed that the ubiquitin ligase COP1 (RFWD2; 608067)
targeted 14-3-3-sigma for ubiquitin-mediated degradation in human cell
lines. The COP9 signalosome subunit COPS6 (614729) stabilized COP1 by
reducing COP1 autoubiquitination, resulting in elevated 14-3-3-sigma
ubiquitination and degradation.
BIOCHEMICAL FEATURES
The 14-3-3 family of proteins mediates signal transduction by binding to
phosphoserine-containing proteins. Using phosphoserine-oriented peptide
libraries to probe all mammalian and yeast 14-3-3s, Yaffe et al. (1997)
identified 2 different binding motifs, RSXpSXP and RXY/FXpSXP, present
in nearly all known 14-3-3 binding proteins. The crystal structure of
YWHAZ (601288) complexed with the phosphoserine motif in polyoma
middle-T was determined to 2.6-angstrom resolution. The authors showed
that the 14-3-3 dimer binds tightly to single molecules containing
tandem repeats of phosphoserine motifs, implicating bidentate
association as a signaling mechanism with molecules such as Raf, BAD
(603167), and Cbl.
ANIMAL MODEL
Stratifin is highly expressed in differentiating epidermis and mediates
cell cycle arrest. To extend understanding of skin development, Herron
et al. (2005) set out to identify the causal mutation in 'repeated
epilation' (Er) mutant mice. The heterozygous mutant (Er/+) mouse was
originally identified in the offspring of a male exposed to gamma
radiation; the mutant had a disheveled appearance at 3 weeks of age.
Older heterozygous mice had an increased incidence of papillomas and
squamous cell carcinomas. Linkage studies localized the Er gene to mouse
chromosome 4 in an 820-kb region containing 22 genes. Among these genes,
Sfn was considered a good candidate for underlying the Er mutation
because it has a role in keratinocyte differentiation and because Sfn
expression is abnormal in epithelial cancers. Sequencing of the Sfn open
reading frame in genomic DNA from homozygous Er/Er and wildtype mice
detected a single T insertion at basepair 622 in homozygous mutant mice.
This frameshift mutation at amino acid 207 truncates the C terminus of
the protein encoded by the Er allele, eliminating residues required for
ligand interaction and the nuclear export sequence.
By gene expression analysis of skin and embryonic fibroblasts from
wildtype and Er mice, Li et al. (2005) identified a 1-bp insertion
(642insT) in the Sfn gene that results in the Er phenotype. The
insertion causes a frameshift leading to a truncated protein lacking 40
amino acids at the C terminus. Li et al. (2005) noted that Er/+ adult
mice showed repeated hair loss, whereas Er/Er mutant mice died at birth
due to respiratory distress and skin defects, with hyperplastic
epidermis, failure of keratinocyte differentiation, and abnormal
craniofacial development. Ectopic overexpression of Sfn in Er/Er
keratinocytes rescued the defects of keratinocyte differentiation.
*FIELD* RF
1. Chan, T. A.; Hermeking, H.; Langauer, C.; Kinzler, K. W.; Vogelstein,
B.: 14-3-3-sigma is required to prevent mitotic catastrophe after
DNA damage. Nature 401: 616-620, 1999.
2. Choi, H. H.; Gully, C.; Su, C.-H.; Velazquez-Torres, G.; Chou,
P.-C.; Tseng, C.; Zhao, R.; Phan, L.; Shaiken, T.; Chen, J.; Yeung,
S. C.; Lee, M.-H.: COP9 signalosome subunit 6 stabilizes COP1, which
functions as an E3 ubiquitin ligase for 14-3-3-sigma. Oncogene 30:
4791-4801, 2011.
3. Ferguson, A. T.; Evron, E.; Umbricht, C. B.; Pandita, T. K.; Chan,
T. A.; Hermeking, H.; Marks, J. R.; Lambers, A. R.; Futreal, P. A.;
Stampfer, M. R.; Sukumar, S.: High frequency of hypermethylation
at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc.
Nat. Acad. Sci. 97: 6049-6054, 2000.
4. Hermeking, H.; Lengauer, C.; Polyak, K.; He, T.-C.; Zhang, L.;
Thiagalingam, S.; Kinzler, K. W.; Vogelstein, B.: 14-3-3-sigma is
a p53-regulated inhibitor of G2/M progression. Molec. Cell 1: 3-11,
1997.
5. Herron, B. J.; Liddell, R. A.; Parker, A.; Grant, S.; Kinne, J.;
Fisher, J. K.; Siracusa, L. D.: A mutation in stratifin is responsible
for the repeated epilation (Er) phenotype in mice. Nature Genet. 37:
1210-1212, 2005.
6. Leffers, H.; Madsen, P.; Rasmussen, H. H.; Honore, B.; Andersen,
A. H.; Walbum, E.; Vandekerckhove, J.; Celis, J. E.: Molecular cloning
and expression of the transformation sensitive epithelial marker stratifin:
a member of a protein family that has been involved in the protein
kinase C signalling pathway. J. Molec. Biol. 231: 982-998, 1993.
7. Li, Q.; Lu, Q.; Estepa, G.; Verma, I. M.: Identification of 14-3-3-sigma
mutation causing cutaneous abnormality in repeated-epilation mutant
mouse. Proc. Nat. Acad. Sci. 102: 15977-15982, 2005.
8. Urano, T.; Saito, T.; Tsukui, T.; Fujita, M.; Hosoi, T.; Muramatsu,
M.; Ouchi, Y.; Inoue, S.: Efp targets 14-3-3-sigma for proteolysis
and promotes breast tumour growth. Nature 417: 871-875, 2002.
9. Wilker, E. W.; van Vugt, M. A. T. M.; Artim, S. A.; Huang, P. H.;
Petersen, C. P.; Reinhardt, H. C.; Feng, Y.; Sharp, P. A.; Sonenberg,
N.; White, F. M.; Yaffe, M. B.: 14-3-3-sigma controls mitotic translation
to facilitate cytokinesis. Nature 446: 329-332, 2007.
10. Yaffe, M. B.; Rittinger, K.; Volinia, S.; Caron, P. R.; Aitken,
A.; Leffers, H.; Gamblin, S. J.; Smerdon, S. J.; Cantley, L. C.:
The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91:
961-971, 1997.
11. Zhu, F.; Xia, X.; Liu, B.; Shen, J.; Hu, Y.; Person, M.; Hu, Y.
: IKK-alpha shields 14-3-3-sigma, a G2/M cell cycle checkpoint gene,
from hypermethylation, preventing its silencing. Molec. Cell 27:
214-227, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 7/11/2012
Patricia A. Hartz - updated: 9/19/2007
Cassandra L. Kniffin - updated: 6/11/2007
Ada Hamosh - updated: 5/1/2007
Anne M. Stumpf - updated: 11/2/2005
Victor A. McKusick - updated: 11/1/2005
Ada Hamosh - updated: 7/12/2002
Victor A. McKusick - updated: 8/4/2000
Ada Hamosh - updated: 10/18/1999
Stylianos E. Antonarakis - updated: 2/20/1998
*FIELD* CD
Alan F. Scott: 6/3/1996
*FIELD* ED
mgross: 02/05/2013
mgross: 7/18/2012
terry: 7/11/2012
mgross: 9/28/2007
terry: 9/19/2007
wwang: 7/9/2007
ckniffin: 6/11/2007
alopez: 5/7/2007
terry: 5/1/2007
alopez: 11/2/2005
terry: 11/1/2005
tkritzer: 1/5/2004
alopez: 7/16/2002
terry: 7/12/2002
mcapotos: 8/10/2000
mcapotos: 8/8/2000
terry: 8/4/2000
alopez: 10/20/1999
terry: 10/18/1999
terry: 11/13/1998
alopez: 10/20/1998
dholmes: 2/20/1998
terry: 6/3/1996
mark: 6/3/1996