Full text data of EZR
EZR
(VIL2)
[Confidence: high (present in two of the MS resources)]
Ezrin (Cytovillin; Villin-2; p81)
Ezrin (Cytovillin; Villin-2; p81)
UniProt
P15311
ID EZRI_HUMAN Reviewed; 586 AA.
AC P15311; E1P5A8; P23714; Q4VX75; Q96CU8; Q9NSJ4;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 06-FEB-2007, sequence version 4.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=Ezrin;
DE AltName: Full=Cytovillin;
DE AltName: Full=Villin-2;
DE AltName: Full=p81;
GN Name=EZR; Synonyms=VIL2;
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], PARTIAL PROTEIN SEQUENCE, AND VARIANT
RP VAL-532.
RX PubMed=2591371;
RA Gould K.L., Bretscher A., Esch F.S., Hunter T.;
RT "cDNA cloning and sequencing of the protein-tyrosine kinase substrate,
RT ezrin, reveals homology to band 4.1.";
RL EMBO J. 8:4133-4142(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-532.
RC TISSUE=Placenta;
RX PubMed=2674140;
RA Turunen O., Winqvist R., Pakkanen R., Grzeschik K.-H., Wahlstroem T.,
RA Vaheri A.;
RT "Cytovillin, a microvillar Mr 75,000 protein. cDNA sequence,
RT prokaryotic expression, and chromosomal localization.";
RL J. Biol. Chem. 264:16727-16732(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
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 172-180 AND 343-350.
RX PubMed=8713105; DOI=10.1006/bbrc.1996.1082;
RA Egerton M., Moritz R.L., Druker B., Kelso A., Simpson R.J.;
RT "Identification of the 70kD heat shock cognate protein (Hsc70) and
RT alpha-actinin-1 as novel phosphotyrosine-containing proteins in T
RT lymphocytes.";
RL Biochem. Biophys. Res. Commun. 224:666-674(1996).
RN [8]
RP PROTEIN SEQUENCE OF 264-273; 428-435 AND 530-542, AND MASS
RP SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [9]
RP PHOSPHORYLATION BY PDGFR.
RX PubMed=1382070;
RA Krieg J., Hunter T.;
RT "Identification of the two major epidermal growth factor-induced
RT tyrosine phosphorylation sites in the microvillar core protein
RT ezrin.";
RL J. Biol. Chem. 267:19258-19265(1992).
RN [10]
RP PHOSPHORYLATION.
RX PubMed=1381389;
RA Egerton M., Burgess W.H., Chen D., Druker B.J., Bretscher A.,
RA Samelson L.E.;
RT "Identification of ezrin as an 81-kDa tyrosine-phosphorylated protein
RT in T cells.";
RL J. Immunol. 149:1847-1852(1992).
RN [11]
RP INTERACTION WITH SLC9A3R1.
RX PubMed=9314537; DOI=10.1083/jcb.139.1.169;
RA Reczek D., Berryman M., Bretscher A.;
RT "Identification of EBP50: a PDZ-containing phosphoprotein that
RT associates with members of the ezrin-radixin-moesin family.";
RL J. Cell Biol. 139:169-179(1997).
RN [12]
RP INTERACTION WITH SCYL3.
RC TISSUE=Kidney;
RX PubMed=12651155; DOI=10.1016/S0014-4827(02)00054-X;
RA Sullivan A., Uff C.R., Isacke C.M., Thorne R.F.;
RT "PACE-1, a novel protein that interacts with the C-terminal domain of
RT ezrin.";
RL Exp. Cell Res. 284:224-238(2003).
RN [13]
RP INTERACTION WITH S100P.
RX PubMed=12808036; DOI=10.1091/mbc.E02-09-0553;
RA Koltzscher M., Neumann C., Konig S., Gerke V.;
RT "Ca2+-dependent binding and activation of dormant ezrin by dimeric
RT S100P.";
RL Mol. Biol. Cell 14:2372-2384(2003).
RN [14]
RP INTERACTION WITH TMEM8B.
RX PubMed=15498789; DOI=10.1093/carcin/bgh312;
RA Ma J., Zhou J., Fan S., Wang L.-L., Li X.-L., Yan Q., Zhou M.,
RA Liu H.-Y., Zhang Q., Zhou H., Gan K., Li Z., Peng C., Xiong W.,
RA Tan C., Shen S.-R., Yang J., Li J., Li G.-Y.;
RT "Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion
RT modulation in nasopharyngeal carcinoma cells.";
RL Carcinogenesis 26:281-291(2005).
RN [15]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=15797715; DOI=10.1016/j.mcn.2004.11.014;
RA Groenholm M., Teesalu T., Tyynelaa J., Piltti K., Boehling T.,
RA Wartiovaara K., Vaheri A., Carpen O.;
RT "Characterization of the NF2 protein merlin and the ERM protein ezrin
RT in human, rat, and mouse central nervous system.";
RL Mol. Cell. Neurosci. 28:683-693(2005).
RN [16]
RP INTERACTION WITH PODXL.
RX PubMed=17616675; DOI=10.1158/0008-5472.CAN-06-3575;
RA Sizemore S., Cicek M., Sizemore N., Ng K.P., Casey G.;
RT "Podocalyxin increases the aggressive phenotype of breast and prostate
RT cancer cells in vitro through its interaction with ezrin.";
RL Cancer Res. 67:6183-6191(2007).
RN [17]
RP FUNCTION, AND INTERACTION WITH PLEKHG6.
RX PubMed=17881735; DOI=10.1091/mbc.E06-12-1144;
RA D'Angelo R., Aresta S., Blangy A., Del Maestro L., Louvard D.,
RA Arpin M.;
RT "Interaction of ezrin with the novel guanine nucleotide exchange
RT factor PLEKHG6 promotes RhoG-dependent apical cytoskeleton
RT rearrangements in epithelial cells.";
RL Mol. Biol. Cell 18:4780-4793(2007).
RN [18]
RP INTERACTION WITH FES/FPS, PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=18046454; DOI=10.1038/sj.emboj.7601943;
RA Naba A., Reverdy C., Louvard D., Arpin M.;
RT "Spatial recruitment and activation of the Fes kinase by ezrin
RT promotes HGF-induced cell scattering.";
RL EMBO J. 27:38-50(2008).
RN [19]
RP FUNCTION, AND PHOSPHORYLATION AT THR-567.
RX PubMed=18270268; DOI=10.1242/jcs.016246;
RA Wald F.A., Oriolo A.S., Mashukova A., Fregien N.L., Langshaw A.H.,
RA Salas P.J.;
RT "Atypical protein kinase C (iota) activates ezrin in the apical domain
RT of intestinal epithelial cells.";
RL J. Cell Sci. 121:644-654(2008).
RN [20]
RP FUNCTION, AND INTERACTION WITH S100P.
RX PubMed=19111582; DOI=10.1016/j.bbamcr.2008.11.012;
RA Austermann J., Nazmi A.R., Heil A., Fritz G., Kolinski M., Filipek S.,
RA Gerke V.;
RT "Generation and characterization of a novel, permanently active S100P
RT mutant.";
RL Biochim. Biophys. Acta 1793:1078-1085(2009).
RN [21]
RP INTERACTION WITH MCC.
RX PubMed=19555689; DOI=10.1016/j.febslet.2009.06.034;
RA Arnaud C., Sebbagh M., Nola S., Audebert S., Bidaut G., Hermant A.,
RA Gayet O., Dusetti N.J., Ollendorff V., Santoni M.J., Borg J.P.,
RA Lecine P.;
RT "MCC, a new interacting protein for Scrib, is required for cell
RT migration in epithelial cells.";
RL FEBS Lett. 583:2326-2332(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-60, 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 [23]
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 [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-535, 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 [25]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-297.
RX PubMed=12429733; DOI=10.1074/jbc.M210601200;
RA Smith W.J., Nassar N., Bretscher A., Cerione R.A., Karplus P.A.;
RT "Structure of the active N-terminal domain of Ezrin. Conformational
RT and mobility changes identify keystone interactions.";
RL J. Biol. Chem. 278:4949-4956(2003).
CC -!- FUNCTION: Probably involved in connections of major cytoskeletal
CC structures to the plasma membrane. In epithelial cells, required
CC for the formation of microvilli and membrane ruffles on the apical
CC pole. Along with PLEKHG6, required for normal macropinocytosis.
CC -!- ENZYME REGULATION: A head-to-tail association, of the N-terminal
CC and C-terminal halves results in a closed conformation (inactive
CC form) which is incapable of actin or membrane-binding (By
CC similarity).
CC -!- SUBUNIT: Interacts with MPP5 and SLC9A3R2. Found in a complex with
CC EZR, PODXL and SLC9A3R2 (By similarity). Interacts with MCC,
CC PLEKHG6, PODXL, SCYL3/PACE1, SLC9A3R1 and TMEM8B. Interacts (when
CC phosphorylated) with FES/FPS. Interacts with dimeric S100P, the
CC interaction may be activating through unmasking of F-actin binding
CC sites.
CC -!- INTERACTION:
CC P07384:CAPN1; NbExp=2; IntAct=EBI-1056902, EBI-1542113;
CC P07332:FES; NbExp=8; IntAct=EBI-1056902, EBI-1055635;
CC Q00987:MDM2; NbExp=3; IntAct=EBI-1056902, EBI-389668;
CC Q8IZE3:SCYL3; NbExp=4; IntAct=EBI-1056902, EBI-1380680;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Peripheral membrane
CC protein; Cytoplasmic side. Cell projection. Cell projection,
CC microvillus membrane; Peripheral membrane protein; Cytoplasmic
CC side. Cell projection, ruffle membrane; Peripheral membrane
CC protein; Cytoplasmic side. Cytoplasm, cell cortex. Cytoplasm,
CC cytoskeleton. Note=Localization to the apical membrane of parietal
CC cells depends on the interaction with MPP5. Localizes to cell
CC extensions and peripheral processes of astrocytes (By similarity).
CC Microvillar peripheral membrane protein (cytoplasmic side).
CC -!- TISSUE SPECIFICITY: Expressed in cerebral cortex, basal ganglia,
CC hippocampus, hypophysis, and optic nerve. Weakly expressed in
CC brain stem and diencephalon. Stronger expression was detected in
CC gray matter of frontal lobe compared to white matter (at protein
CC level). Component of the microvilli of intestinal epithelial
CC cells. Preferentially expressed in astrocytes of hippocampus,
CC frontal cortex, thalamus, parahippocampal cortex, amygdala,
CC insula, and corpus callosum. Not detected in neurons in most
CC tissues studied.
CC -!- DEVELOPMENTAL STAGE: Very strong staining is detected in the
CC Purkinje cell layer and in part of the molecular layer of the
CC infant brain compared to adult brain.
CC -!- PTM: Phosphorylated by tyrosine-protein kinases. Phosphorylation
CC by ROCK2 suppresses the head-to-tail association of the N-terminal
CC and C-terminal halves resulting in an opened conformation which is
CC capable of actin and membrane-binding (By similarity).
CC -!- SIMILARITY: Contains 1 FERM domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA61278.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAB82418.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; X51521; CAA35893.1; -; mRNA.
DR EMBL; J05021; AAA61278.1; ALT_INIT; mRNA.
DR EMBL; AL162086; CAB82418.1; ALT_INIT; mRNA.
DR EMBL; AL589931; CAI95307.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW47647.1; -; Genomic_DNA.
DR EMBL; BC013903; AAH13903.1; -; mRNA.
DR PIR; A34400; A34400.
DR RefSeq; NP_001104547.1; NM_001111077.1.
DR RefSeq; NP_003370.2; NM_003379.4.
DR UniGene; Hs.487027; -.
DR PDB; 1NI2; X-ray; 2.30 A; A/B=2-297.
DR PDBsum; 1NI2; -.
DR ProteinModelPortal; P15311; -.
DR SMR; P15311; 1-586.
DR DIP; DIP-38868N; -.
DR IntAct; P15311; 24.
DR MINT; MINT-195721; -.
DR STRING; 9606.ENSP00000338934; -.
DR ChEMBL; CHEMBL1932896; -.
DR PhosphoSite; P15311; -.
DR DMDM; 125987826; -.
DR DOSAC-COBS-2DPAGE; P15311; -.
DR REPRODUCTION-2DPAGE; IPI00843975; -.
DR SWISS-2DPAGE; P15311; -.
DR PaxDb; P15311; -.
DR PRIDE; P15311; -.
DR DNASU; 7430; -.
DR Ensembl; ENST00000337147; ENSP00000338934; ENSG00000092820.
DR Ensembl; ENST00000367075; ENSP00000356042; ENSG00000092820.
DR GeneID; 7430; -.
DR KEGG; hsa:7430; -.
DR UCSC; uc003qrt.4; human.
DR CTD; 7430; -.
DR GeneCards; GC06M159186; -.
DR HGNC; HGNC:12691; EZR.
DR HPA; CAB004035; -.
DR HPA; CAB047324; -.
DR HPA; HPA021616; -.
DR MIM; 123900; gene.
DR neXtProt; NX_P15311; -.
DR PharmGKB; PA162385512; -.
DR eggNOG; NOG236035; -.
DR HOGENOM; HOG000007113; -.
DR HOVERGEN; HBG002185; -.
DR KO; K08007; -.
DR OMA; LQDEGTE; -.
DR OrthoDB; EOG7BGHK6; -.
DR PhylomeDB; P15311; -.
DR Reactome; REACT_111045; Developmental Biology.
DR ChiTaRS; EZR; human.
DR EvolutionaryTrace; P15311; -.
DR GeneWiki; Ezrin; -.
DR GenomeRNAi; 7430; -.
DR NextBio; 29100; -.
DR PRO; PR:P15311; -.
DR ArrayExpress; P15311; -.
DR Bgee; P15311; -.
DR CleanEx; HS_EZR; -.
DR Genevestigator; P15311; -.
DR GO; GO:0005884; C:actin filament; IDA:HGNC.
DR GO; GO:0045177; C:apical part of cell; IDA:BHF-UCL.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; TAS:HGNC.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0019898; C:extrinsic to membrane; IDA:UniProtKB.
DR GO; GO:0030175; C:filopodium; IDA:BHF-UCL.
DR GO; GO:0005932; C:microtubule basal body; IEA:Ensembl.
DR GO; GO:0005902; C:microvillus; IDA:BHF-UCL.
DR GO; GO:0031528; C:microvillus membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0001726; C:ruffle; IDA:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001931; C:uropod; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0051017; P:actin filament bundle assembly; IDA:UniProtKB.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007016; P:cytoskeletal anchoring at plasma membrane; NAS:UniProtKB.
DR GO; GO:0030855; P:epithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0035088; P:establishment or maintenance of apical/basal cell polarity; IEA:Ensembl.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IEP:BHF-UCL.
DR GO; GO:0022614; P:membrane to membrane docking; IEP:BHF-UCL.
DR GO; GO:0008360; P:regulation of cell shape; IEA:UniProtKB-KW.
DR Gene3D; 1.20.80.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR019750; Band_41_fam.
DR InterPro; IPR011174; ERM.
DR InterPro; IPR011259; ERM_C_dom.
DR InterPro; IPR000798; Ez/rad/moesin_like.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_3-hlx.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR019747; FERM_CS.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR018979; FERM_N.
DR InterPro; IPR018980; FERM_PH-like_C.
DR InterPro; IPR008954; Moesin_tail.
DR InterPro; IPR011993; PH_like_dom.
DR Pfam; PF00769; ERM; 1.
DR Pfam; PF09380; FERM_C; 1.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF09379; FERM_N; 1.
DR PIRSF; PIRSF002305; ERM; 1.
DR PRINTS; PR00935; BAND41.
DR PRINTS; PR00661; ERMFAMILY.
DR SMART; SM00295; B41; 1.
DR SUPFAM; SSF47031; SSF47031; 1.
DR SUPFAM; SSF48678; SSF48678; 1.
DR PROSITE; PS00660; FERM_1; 1.
DR PROSITE; PS00661; FERM_2; 1.
DR PROSITE; PS50057; FERM_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Cell projection; Cell shape;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Membrane; Phosphoprotein; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 586 Ezrin.
FT /FTId=PRO_0000219408.
FT DOMAIN 2 295 FERM.
FT REGION 244 586 Interaction with SCYL3.
FT MOD_RES 60 60 N6-acetyllysine.
FT MOD_RES 146 146 Phosphotyrosine; by PDGFR.
FT MOD_RES 354 354 Phosphotyrosine; by PDGFR.
FT MOD_RES 535 535 Phosphoserine.
FT MOD_RES 567 567 Phosphothreonine; by ROCK2 and PKC/PRKCI
FT (Probable).
FT VARIANT 180 180 R -> C (in dbSNP:rs3103004).
FT /FTId=VAR_030572.
FT VARIANT 494 494 A -> P (in dbSNP:rs2230143).
FT /FTId=VAR_030573.
FT VARIANT 532 532 L -> V.
FT /FTId=VAR_015112.
FT STRAND 5 11
FT STRAND 14 20
FT HELIX 26 37
FT HELIX 42 44
FT STRAND 45 51
FT STRAND 56 58
FT STRAND 61 64
FT HELIX 65 67
FT STRAND 74 84
FT HELIX 89 92
FT HELIX 96 111
FT HELIX 119 134
FT TURN 139 141
FT STRAND 146 149
FT HELIX 155 160
FT HELIX 165 178
FT HELIX 184 195
FT TURN 199 202
FT STRAND 204 210
FT STRAND 215 220
FT STRAND 222 229
FT STRAND 232 235
FT STRAND 237 242
FT STRAND 245 253
FT STRAND 255 262
FT STRAND 268 270
FT HELIX 274 293
SQ SEQUENCE 586 AA; 69413 MW; F1B592CF49A7CC46 CRC64;
MPKPINVRVT TMDAELEFAI QPNTTGKQLF DQVVKTIGLR EVWYFGLHYV DNKGFPTWLK
LDKKVSAQEV RKENPLQFKF RAKFYPEDVA EELIQDITQK LFFLQVKEGI LSDEIYCPPE
TAVLLGSYAV QAKFGDYNKE VHKSGYLSSE RLIPQRVMDQ HKLTRDQWED RIQVWHAEHR
GMLKDNAMLE YLKIAQDLEM YGINYFEIKN KKGTDLWLGV DALGLNIYEK DDKLTPKIGF
PWSEIRNISF NDKKFVIKPI DKKAPDFVFY APRLRINKRI LQLCMGNHEL YMRRRKPDTI
EVQQMKAQAR EEKHQKQLER QQLETEKKRR ETVEREKEQM MREKEELMLR LQDYEEKTKK
AERELSEQIQ RALQLEEERK RAQEEAERLE ADRMAALRAK EELERQAVDQ IKSQEQLAAE
LAEYTAKIAL LEEARRRKED EVEEWQHRAK EAQDDLVKTK EELHLVMTAP PPPPPPVYEP
VSYHVQESLQ DEGAEPTGYS AELSSEGIRD DRNEEKRITE AEKNERVQRQ LLTLSSELSQ
ARDENKRTHN DIIHNENMRQ GRDKYKTLRQ IRQGNTKQRI DEFEAL
//
ID EZRI_HUMAN Reviewed; 586 AA.
AC P15311; E1P5A8; P23714; Q4VX75; Q96CU8; Q9NSJ4;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 06-FEB-2007, sequence version 4.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=Ezrin;
DE AltName: Full=Cytovillin;
DE AltName: Full=Villin-2;
DE AltName: Full=p81;
GN Name=EZR; Synonyms=VIL2;
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], PARTIAL PROTEIN SEQUENCE, AND VARIANT
RP VAL-532.
RX PubMed=2591371;
RA Gould K.L., Bretscher A., Esch F.S., Hunter T.;
RT "cDNA cloning and sequencing of the protein-tyrosine kinase substrate,
RT ezrin, reveals homology to band 4.1.";
RL EMBO J. 8:4133-4142(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-532.
RC TISSUE=Placenta;
RX PubMed=2674140;
RA Turunen O., Winqvist R., Pakkanen R., Grzeschik K.-H., Wahlstroem T.,
RA Vaheri A.;
RT "Cytovillin, a microvillar Mr 75,000 protein. cDNA sequence,
RT prokaryotic expression, and chromosomal localization.";
RL J. Biol. Chem. 264:16727-16732(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
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 172-180 AND 343-350.
RX PubMed=8713105; DOI=10.1006/bbrc.1996.1082;
RA Egerton M., Moritz R.L., Druker B., Kelso A., Simpson R.J.;
RT "Identification of the 70kD heat shock cognate protein (Hsc70) and
RT alpha-actinin-1 as novel phosphotyrosine-containing proteins in T
RT lymphocytes.";
RL Biochem. Biophys. Res. Commun. 224:666-674(1996).
RN [8]
RP PROTEIN SEQUENCE OF 264-273; 428-435 AND 530-542, AND MASS
RP SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [9]
RP PHOSPHORYLATION BY PDGFR.
RX PubMed=1382070;
RA Krieg J., Hunter T.;
RT "Identification of the two major epidermal growth factor-induced
RT tyrosine phosphorylation sites in the microvillar core protein
RT ezrin.";
RL J. Biol. Chem. 267:19258-19265(1992).
RN [10]
RP PHOSPHORYLATION.
RX PubMed=1381389;
RA Egerton M., Burgess W.H., Chen D., Druker B.J., Bretscher A.,
RA Samelson L.E.;
RT "Identification of ezrin as an 81-kDa tyrosine-phosphorylated protein
RT in T cells.";
RL J. Immunol. 149:1847-1852(1992).
RN [11]
RP INTERACTION WITH SLC9A3R1.
RX PubMed=9314537; DOI=10.1083/jcb.139.1.169;
RA Reczek D., Berryman M., Bretscher A.;
RT "Identification of EBP50: a PDZ-containing phosphoprotein that
RT associates with members of the ezrin-radixin-moesin family.";
RL J. Cell Biol. 139:169-179(1997).
RN [12]
RP INTERACTION WITH SCYL3.
RC TISSUE=Kidney;
RX PubMed=12651155; DOI=10.1016/S0014-4827(02)00054-X;
RA Sullivan A., Uff C.R., Isacke C.M., Thorne R.F.;
RT "PACE-1, a novel protein that interacts with the C-terminal domain of
RT ezrin.";
RL Exp. Cell Res. 284:224-238(2003).
RN [13]
RP INTERACTION WITH S100P.
RX PubMed=12808036; DOI=10.1091/mbc.E02-09-0553;
RA Koltzscher M., Neumann C., Konig S., Gerke V.;
RT "Ca2+-dependent binding and activation of dormant ezrin by dimeric
RT S100P.";
RL Mol. Biol. Cell 14:2372-2384(2003).
RN [14]
RP INTERACTION WITH TMEM8B.
RX PubMed=15498789; DOI=10.1093/carcin/bgh312;
RA Ma J., Zhou J., Fan S., Wang L.-L., Li X.-L., Yan Q., Zhou M.,
RA Liu H.-Y., Zhang Q., Zhou H., Gan K., Li Z., Peng C., Xiong W.,
RA Tan C., Shen S.-R., Yang J., Li J., Li G.-Y.;
RT "Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion
RT modulation in nasopharyngeal carcinoma cells.";
RL Carcinogenesis 26:281-291(2005).
RN [15]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=15797715; DOI=10.1016/j.mcn.2004.11.014;
RA Groenholm M., Teesalu T., Tyynelaa J., Piltti K., Boehling T.,
RA Wartiovaara K., Vaheri A., Carpen O.;
RT "Characterization of the NF2 protein merlin and the ERM protein ezrin
RT in human, rat, and mouse central nervous system.";
RL Mol. Cell. Neurosci. 28:683-693(2005).
RN [16]
RP INTERACTION WITH PODXL.
RX PubMed=17616675; DOI=10.1158/0008-5472.CAN-06-3575;
RA Sizemore S., Cicek M., Sizemore N., Ng K.P., Casey G.;
RT "Podocalyxin increases the aggressive phenotype of breast and prostate
RT cancer cells in vitro through its interaction with ezrin.";
RL Cancer Res. 67:6183-6191(2007).
RN [17]
RP FUNCTION, AND INTERACTION WITH PLEKHG6.
RX PubMed=17881735; DOI=10.1091/mbc.E06-12-1144;
RA D'Angelo R., Aresta S., Blangy A., Del Maestro L., Louvard D.,
RA Arpin M.;
RT "Interaction of ezrin with the novel guanine nucleotide exchange
RT factor PLEKHG6 promotes RhoG-dependent apical cytoskeleton
RT rearrangements in epithelial cells.";
RL Mol. Biol. Cell 18:4780-4793(2007).
RN [18]
RP INTERACTION WITH FES/FPS, PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=18046454; DOI=10.1038/sj.emboj.7601943;
RA Naba A., Reverdy C., Louvard D., Arpin M.;
RT "Spatial recruitment and activation of the Fes kinase by ezrin
RT promotes HGF-induced cell scattering.";
RL EMBO J. 27:38-50(2008).
RN [19]
RP FUNCTION, AND PHOSPHORYLATION AT THR-567.
RX PubMed=18270268; DOI=10.1242/jcs.016246;
RA Wald F.A., Oriolo A.S., Mashukova A., Fregien N.L., Langshaw A.H.,
RA Salas P.J.;
RT "Atypical protein kinase C (iota) activates ezrin in the apical domain
RT of intestinal epithelial cells.";
RL J. Cell Sci. 121:644-654(2008).
RN [20]
RP FUNCTION, AND INTERACTION WITH S100P.
RX PubMed=19111582; DOI=10.1016/j.bbamcr.2008.11.012;
RA Austermann J., Nazmi A.R., Heil A., Fritz G., Kolinski M., Filipek S.,
RA Gerke V.;
RT "Generation and characterization of a novel, permanently active S100P
RT mutant.";
RL Biochim. Biophys. Acta 1793:1078-1085(2009).
RN [21]
RP INTERACTION WITH MCC.
RX PubMed=19555689; DOI=10.1016/j.febslet.2009.06.034;
RA Arnaud C., Sebbagh M., Nola S., Audebert S., Bidaut G., Hermant A.,
RA Gayet O., Dusetti N.J., Ollendorff V., Santoni M.J., Borg J.P.,
RA Lecine P.;
RT "MCC, a new interacting protein for Scrib, is required for cell
RT migration in epithelial cells.";
RL FEBS Lett. 583:2326-2332(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-60, 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 [23]
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 [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-535, 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 [25]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-297.
RX PubMed=12429733; DOI=10.1074/jbc.M210601200;
RA Smith W.J., Nassar N., Bretscher A., Cerione R.A., Karplus P.A.;
RT "Structure of the active N-terminal domain of Ezrin. Conformational
RT and mobility changes identify keystone interactions.";
RL J. Biol. Chem. 278:4949-4956(2003).
CC -!- FUNCTION: Probably involved in connections of major cytoskeletal
CC structures to the plasma membrane. In epithelial cells, required
CC for the formation of microvilli and membrane ruffles on the apical
CC pole. Along with PLEKHG6, required for normal macropinocytosis.
CC -!- ENZYME REGULATION: A head-to-tail association, of the N-terminal
CC and C-terminal halves results in a closed conformation (inactive
CC form) which is incapable of actin or membrane-binding (By
CC similarity).
CC -!- SUBUNIT: Interacts with MPP5 and SLC9A3R2. Found in a complex with
CC EZR, PODXL and SLC9A3R2 (By similarity). Interacts with MCC,
CC PLEKHG6, PODXL, SCYL3/PACE1, SLC9A3R1 and TMEM8B. Interacts (when
CC phosphorylated) with FES/FPS. Interacts with dimeric S100P, the
CC interaction may be activating through unmasking of F-actin binding
CC sites.
CC -!- INTERACTION:
CC P07384:CAPN1; NbExp=2; IntAct=EBI-1056902, EBI-1542113;
CC P07332:FES; NbExp=8; IntAct=EBI-1056902, EBI-1055635;
CC Q00987:MDM2; NbExp=3; IntAct=EBI-1056902, EBI-389668;
CC Q8IZE3:SCYL3; NbExp=4; IntAct=EBI-1056902, EBI-1380680;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Peripheral membrane
CC protein; Cytoplasmic side. Cell projection. Cell projection,
CC microvillus membrane; Peripheral membrane protein; Cytoplasmic
CC side. Cell projection, ruffle membrane; Peripheral membrane
CC protein; Cytoplasmic side. Cytoplasm, cell cortex. Cytoplasm,
CC cytoskeleton. Note=Localization to the apical membrane of parietal
CC cells depends on the interaction with MPP5. Localizes to cell
CC extensions and peripheral processes of astrocytes (By similarity).
CC Microvillar peripheral membrane protein (cytoplasmic side).
CC -!- TISSUE SPECIFICITY: Expressed in cerebral cortex, basal ganglia,
CC hippocampus, hypophysis, and optic nerve. Weakly expressed in
CC brain stem and diencephalon. Stronger expression was detected in
CC gray matter of frontal lobe compared to white matter (at protein
CC level). Component of the microvilli of intestinal epithelial
CC cells. Preferentially expressed in astrocytes of hippocampus,
CC frontal cortex, thalamus, parahippocampal cortex, amygdala,
CC insula, and corpus callosum. Not detected in neurons in most
CC tissues studied.
CC -!- DEVELOPMENTAL STAGE: Very strong staining is detected in the
CC Purkinje cell layer and in part of the molecular layer of the
CC infant brain compared to adult brain.
CC -!- PTM: Phosphorylated by tyrosine-protein kinases. Phosphorylation
CC by ROCK2 suppresses the head-to-tail association of the N-terminal
CC and C-terminal halves resulting in an opened conformation which is
CC capable of actin and membrane-binding (By similarity).
CC -!- SIMILARITY: Contains 1 FERM domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA61278.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAB82418.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; X51521; CAA35893.1; -; mRNA.
DR EMBL; J05021; AAA61278.1; ALT_INIT; mRNA.
DR EMBL; AL162086; CAB82418.1; ALT_INIT; mRNA.
DR EMBL; AL589931; CAI95307.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW47647.1; -; Genomic_DNA.
DR EMBL; BC013903; AAH13903.1; -; mRNA.
DR PIR; A34400; A34400.
DR RefSeq; NP_001104547.1; NM_001111077.1.
DR RefSeq; NP_003370.2; NM_003379.4.
DR UniGene; Hs.487027; -.
DR PDB; 1NI2; X-ray; 2.30 A; A/B=2-297.
DR PDBsum; 1NI2; -.
DR ProteinModelPortal; P15311; -.
DR SMR; P15311; 1-586.
DR DIP; DIP-38868N; -.
DR IntAct; P15311; 24.
DR MINT; MINT-195721; -.
DR STRING; 9606.ENSP00000338934; -.
DR ChEMBL; CHEMBL1932896; -.
DR PhosphoSite; P15311; -.
DR DMDM; 125987826; -.
DR DOSAC-COBS-2DPAGE; P15311; -.
DR REPRODUCTION-2DPAGE; IPI00843975; -.
DR SWISS-2DPAGE; P15311; -.
DR PaxDb; P15311; -.
DR PRIDE; P15311; -.
DR DNASU; 7430; -.
DR Ensembl; ENST00000337147; ENSP00000338934; ENSG00000092820.
DR Ensembl; ENST00000367075; ENSP00000356042; ENSG00000092820.
DR GeneID; 7430; -.
DR KEGG; hsa:7430; -.
DR UCSC; uc003qrt.4; human.
DR CTD; 7430; -.
DR GeneCards; GC06M159186; -.
DR HGNC; HGNC:12691; EZR.
DR HPA; CAB004035; -.
DR HPA; CAB047324; -.
DR HPA; HPA021616; -.
DR MIM; 123900; gene.
DR neXtProt; NX_P15311; -.
DR PharmGKB; PA162385512; -.
DR eggNOG; NOG236035; -.
DR HOGENOM; HOG000007113; -.
DR HOVERGEN; HBG002185; -.
DR KO; K08007; -.
DR OMA; LQDEGTE; -.
DR OrthoDB; EOG7BGHK6; -.
DR PhylomeDB; P15311; -.
DR Reactome; REACT_111045; Developmental Biology.
DR ChiTaRS; EZR; human.
DR EvolutionaryTrace; P15311; -.
DR GeneWiki; Ezrin; -.
DR GenomeRNAi; 7430; -.
DR NextBio; 29100; -.
DR PRO; PR:P15311; -.
DR ArrayExpress; P15311; -.
DR Bgee; P15311; -.
DR CleanEx; HS_EZR; -.
DR Genevestigator; P15311; -.
DR GO; GO:0005884; C:actin filament; IDA:HGNC.
DR GO; GO:0045177; C:apical part of cell; IDA:BHF-UCL.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; TAS:HGNC.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0019898; C:extrinsic to membrane; IDA:UniProtKB.
DR GO; GO:0030175; C:filopodium; IDA:BHF-UCL.
DR GO; GO:0005932; C:microtubule basal body; IEA:Ensembl.
DR GO; GO:0005902; C:microvillus; IDA:BHF-UCL.
DR GO; GO:0031528; C:microvillus membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0001726; C:ruffle; IDA:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001931; C:uropod; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0051017; P:actin filament bundle assembly; IDA:UniProtKB.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007016; P:cytoskeletal anchoring at plasma membrane; NAS:UniProtKB.
DR GO; GO:0030855; P:epithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0035088; P:establishment or maintenance of apical/basal cell polarity; IEA:Ensembl.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IEP:BHF-UCL.
DR GO; GO:0022614; P:membrane to membrane docking; IEP:BHF-UCL.
DR GO; GO:0008360; P:regulation of cell shape; IEA:UniProtKB-KW.
DR Gene3D; 1.20.80.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR019750; Band_41_fam.
DR InterPro; IPR011174; ERM.
DR InterPro; IPR011259; ERM_C_dom.
DR InterPro; IPR000798; Ez/rad/moesin_like.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_3-hlx.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR019747; FERM_CS.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR018979; FERM_N.
DR InterPro; IPR018980; FERM_PH-like_C.
DR InterPro; IPR008954; Moesin_tail.
DR InterPro; IPR011993; PH_like_dom.
DR Pfam; PF00769; ERM; 1.
DR Pfam; PF09380; FERM_C; 1.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF09379; FERM_N; 1.
DR PIRSF; PIRSF002305; ERM; 1.
DR PRINTS; PR00935; BAND41.
DR PRINTS; PR00661; ERMFAMILY.
DR SMART; SM00295; B41; 1.
DR SUPFAM; SSF47031; SSF47031; 1.
DR SUPFAM; SSF48678; SSF48678; 1.
DR PROSITE; PS00660; FERM_1; 1.
DR PROSITE; PS00661; FERM_2; 1.
DR PROSITE; PS50057; FERM_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Cell projection; Cell shape;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Membrane; Phosphoprotein; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 586 Ezrin.
FT /FTId=PRO_0000219408.
FT DOMAIN 2 295 FERM.
FT REGION 244 586 Interaction with SCYL3.
FT MOD_RES 60 60 N6-acetyllysine.
FT MOD_RES 146 146 Phosphotyrosine; by PDGFR.
FT MOD_RES 354 354 Phosphotyrosine; by PDGFR.
FT MOD_RES 535 535 Phosphoserine.
FT MOD_RES 567 567 Phosphothreonine; by ROCK2 and PKC/PRKCI
FT (Probable).
FT VARIANT 180 180 R -> C (in dbSNP:rs3103004).
FT /FTId=VAR_030572.
FT VARIANT 494 494 A -> P (in dbSNP:rs2230143).
FT /FTId=VAR_030573.
FT VARIANT 532 532 L -> V.
FT /FTId=VAR_015112.
FT STRAND 5 11
FT STRAND 14 20
FT HELIX 26 37
FT HELIX 42 44
FT STRAND 45 51
FT STRAND 56 58
FT STRAND 61 64
FT HELIX 65 67
FT STRAND 74 84
FT HELIX 89 92
FT HELIX 96 111
FT HELIX 119 134
FT TURN 139 141
FT STRAND 146 149
FT HELIX 155 160
FT HELIX 165 178
FT HELIX 184 195
FT TURN 199 202
FT STRAND 204 210
FT STRAND 215 220
FT STRAND 222 229
FT STRAND 232 235
FT STRAND 237 242
FT STRAND 245 253
FT STRAND 255 262
FT STRAND 268 270
FT HELIX 274 293
SQ SEQUENCE 586 AA; 69413 MW; F1B592CF49A7CC46 CRC64;
MPKPINVRVT TMDAELEFAI QPNTTGKQLF DQVVKTIGLR EVWYFGLHYV DNKGFPTWLK
LDKKVSAQEV RKENPLQFKF RAKFYPEDVA EELIQDITQK LFFLQVKEGI LSDEIYCPPE
TAVLLGSYAV QAKFGDYNKE VHKSGYLSSE RLIPQRVMDQ HKLTRDQWED RIQVWHAEHR
GMLKDNAMLE YLKIAQDLEM YGINYFEIKN KKGTDLWLGV DALGLNIYEK DDKLTPKIGF
PWSEIRNISF NDKKFVIKPI DKKAPDFVFY APRLRINKRI LQLCMGNHEL YMRRRKPDTI
EVQQMKAQAR EEKHQKQLER QQLETEKKRR ETVEREKEQM MREKEELMLR LQDYEEKTKK
AERELSEQIQ RALQLEEERK RAQEEAERLE ADRMAALRAK EELERQAVDQ IKSQEQLAAE
LAEYTAKIAL LEEARRRKED EVEEWQHRAK EAQDDLVKTK EELHLVMTAP PPPPPPVYEP
VSYHVQESLQ DEGAEPTGYS AELSSEGIRD DRNEEKRITE AEKNERVQRQ LLTLSSELSQ
ARDENKRTHN DIIHNENMRQ GRDKYKTLRQ IRQGNTKQRI DEFEAL
//
MIM
123900
*RECORD*
*FIELD* NO
123900
*FIELD* TI
*123900 VILLIN 2; VIL2
;;CYTOVILLIN; CVIL; CVL;;
EZRIN
*FIELD* TX
DESCRIPTION
Cytovillin is a microvillar cytoplasmic peripheral membrane protein that
read moreis expressed strongly in placental syncytiotrophoblasts and in certain
human tumors. It is the same as ezrin, a component of the microvilli of
intestinal epithelial cells that serves as a major cytoplasmic substrate
for certain protein-tyrosine kinases. Ezrin, radixin (RDX; 179410), and
moesin (MSN; 309845), the so-called ERM proteins, act as linkers between
the plasma membrane and the actin cytoskeleton. They are involved in a
variety of cellular functions, such as cell adhesion, migration, and the
organization of cell surface structures. They are highly homologous,
both in protein structure and in functional activity, with
merlin/schwannomin, the NF2 tumor suppressor protein (607379).
CLONING
Winqvist et al. (1989) cloned cytovillin cDNA from a human placental
lambda gt11 library using affinity-purified antibodies. Gould et al.
(1989) cloned and sequenced a human ezrin cDNA. The deduced protein
sequence indicated that ezrin is a highly charged protein with an
overall pI of 6.1 and a calculated molecular mass of 69,000. Using the
cDNA clone to survey the distribution of the ezrin transcript, Pakkanen
and Vaheri (1989) showed that purified cytovillin reacts with antibodies
raised against ezrin. Gould et al. (1989) found the 3.2-kb ezrin mRNA in
the same tissues that are known to express the protein and at the same
relative levels. Highest expression was found in intestine, kidney, and
lung. The cDNA clone hybridized to DNAs from widely divergent organisms,
indicating that the sequence is highly conserved throughout evolution.
Within its N-terminal domain, ezrin showed a high degree of similarity
of amino acid sequence to the erythrocyte cytoskeletal protein band 4.1
(130500).
GENE FUNCTION
The immunologic synapse is the T cell-APC (antigen-presenting cell)
contact site where T-cell receptors, coreceptors, signaling molecules,
and adhesion receptors polarize upon antigen recognition. The formation
of the immunologic synapse is thought to be important for receptor
signal transduction and full T-lymphocyte activation. Using
superantigen-stimulated Jurkat cells and confocal microscopy, Roumier et
al. (2001) demonstrated that ezrin, F-actin (see ACTA1; 102610), and
CD43 (182160) relocalize to the sides, not the center, of the T cell-APC
contact area after T-cell activation, suggesting that ezrin may
contribute to setting the scaffold between the actin cytoskeleton and
transmembrane proteins facilitating cell-cell interactions and receptor
retention.
Using mouse helper T cell lines and confocal microscopy, Allenspach et
al. (2001) determined that the cytoplasmic tail of CD43 is necessary and
sufficient for CD43 removal from the immunologic synapse. In at least
some cells, CD43 is located at the distal pole of the T cell together
with ezrin and moesin. No differences in the behavior of ezrin and
moesin were noted throughout the study. Using cells from Cd43 -/- mice,
Allenspach et al. (2001) observed that ERM proteins move independently
of the large CD43 mucin. Overexpression of a dominant-negative ERM
mutant containing the N-terminal 320 amino acids of ezrin inhibited the
activation-induced movement of CD43 without affecting conjugate
formation. The dominant-negative mutant reduced cytokine production but
not the expression of T-cell activation markers.
Bonilha and Rodriguez-Boulan (2001) identified EBP50 (604990) and SAP97
(601014) as binding partners for ezrin, an actin-binding protein crucial
for morphogenesis of apical microvilli and basolateral infoldings in
retinal pigment epithelial (RPE) cells. Immunofluorescence microscopy
detected a polarized distribution of EBP50 at apical microvilli and of
SAP97 at the basolateral surface of RPE cells, which overlapped with
ezrin.
By 2-hybrid analysis, affinity precipitation, and mutation analysis,
Mykkanen et al. (2001) determined that the alpha-helical region of ezrin
interacted with the C-terminal Ig domains of the
microfilament-associated protein palladin (608092). The palladin-binding
site was masked in dormant wildtype ezrin. By double staining of ezrin
and palladin in several cell lines, Mykkanen et al. (2001) found that
the subcellular localization of ezrin differed between epithelia and
smooth muscle cells. In epithelial cells, such as HeLa, ezrin localized
at the cortical actin skeleton and demonstrated little overlap with
palladin. However, in intestinal smooth muscle cells, ezrin demonstrated
a filamentous staining pattern and partial colocalization with palladin.
Using yeast 2-hybrid analysis of a rat glomerular cDNA library, Takeda
et al. (2001) found that the PDZ-binding motif in the cytoplasmic
C-terminal tail of rat podocalyxin (PODXL; 602632) bound the second PDZ
domain of Nherf2 (SLC9A3R2; 606553). Immunocytochemical analysis
colocalized Nherf2 with podocalyxin and ezrin along the apical domain of
the glomerular epithelial cell membrane. Coimmunoprecipitation analysis
showed that Nherf2 and ezrin formed a multimeric complex with
podocalyxin. The complex interacted with the actin cytoskeleton, and
this interaction was disrupted in glomerular epithelial cells from rats
treated with agents that cause loss of foot processes. Takeda et al.
(2001) concluded that NHERF2 functions as a scaffold protein linking
podocalyxin to ezrin and the actin cytoskeleton.
Yu et al. (2004) established highly and poorly metastatic
rhabdomyosarcoma cell lines derived from a transgenic mouse model
overexpressing Hgf/Sf (142409) and deficient for Ink4a/Arf (600160), in
which skeletal muscle tumors reminiscent of those in embryonic
rhabdomyosarcoma (268210) arise with very high penetrance and short
latency (Sharp et al., 2002). Yu et al. (2004) then used cDNA microarray
analysis of these cell lines to identify a set of genes whose expression
was significantly different between highly and poorly metastatic cells.
Subsequent in vivo functional studies revealed that ezrin and Six1
(601205) have essential roles in determining the metastatic fate of
rhabdomyosarcoma cells. VIL2 and SIX1 expression was enhanced in human
rhabdomyosarcoma tissue, significantly correlating with clinical stage.
By imaging osteosarcoma cells in the lungs of mice, Khanna et al. (2004)
showed that ezrin expression provides an early survival advantage for
cancer cells that reach the lung. AKT (164730) and MAPK3 (601795)
phosphorylation and activity were reduced when ezrin was suppressed.
Ezrin-mediated early metastatic survival was partially dependent on the
activation of MAPK but not AKT. To define the relevance of ezrin in the
biology of metastasis beyond the founding mouse model, Khanna et al.
(2004) examined ezrin expression in dogs that naturally developed
osteosarcoma. High ezrin expression in dog tumors was associated with
early development of metastases. Consistent with these data, Khanna et
al. (2004) found a significant association between high ezrin expression
and poor outcome in pediatric osteosarcoma patients.
Using antigen-activated T cells, Faure et al. (2004) showed that the ERM
proteins are rapidly inactivated through a VAV1 (164875)-RAC1 (602048)
pathway. The resulting disanchoring of the cortical actin cytoskeleton
from the plasma membrane decreased cellular rigidity, leading to more
efficient T cell-APC conjugate formation. The authors concluded that
this pathway favors immunologic synapse formation and the development of
an effective immune response.
Dystroglycan (DAG1; 128239) is part of an adhesion receptor complex
linking the extracellular matrix to the actin cytoskeleton. Spence et
al. (2004) localized beta-dystroglycan to microvilli structures in a
number of cell types where it associated with ezrin, through which it
was able to modulate the actin cytoskeleton and induced peripheral
filopodia and microvilli. Ezrin was able to interact with dystroglycan
through a cluster of basic residues in the juxtamembrane region of
dystroglycan, and mutation of these residues both prevented ezrin
binding and the induction of actin-rich surface protrusions.
GENE STRUCTURE
Majander-Nordenswan et al. (1998) reported the genomic structure and
intron junction sequences of the human ezrin gene. The gene consists of
13 exons and spans approximately 24 kb of genomic DNA. The exons range
in size from 12 bp to 275 bp and the introns from 182 bp to 7 kb. The
genomic structures of ezrin and moesin are highly conserved, suggesting
that they diverged recently.
MAPPING
By Southern blotting of panels of human-mouse somatic cell hybrids,
Turunen et al. (1989) localized the VIL2 gene to 6q22-q27 (or perhaps
6q25-q27). Since the VIL2 gene was not coamplified with the MYB gene
(189990) in colon cancer cell lines, it is probably not located close to
the MYB gene at 6q22-q23. By fluorescence in situ hybridization, Rao et
al. (1994) mapped the VIL2 gene to 6q25-q26. By radiation hybrid
mapping, Majander-Nordenswan et al. (1998) refined the location of the
ezrin gene to the interval between D6S442 and D6S281.
ANIMAL MODEL
Saotome et al. (2004) created mice with a conditional mutation in the
ezrin gene. Homozygous mutant mice were born at submendelian ratios
(about 12%). Despite their normal appearance at birth, they failed to
thrive and did not survive past weaning. The luminal surface of Ez -/-
intestine was covered with cauliflower-shaped villi that appeared to be
aggregates of multiple individual villi. The morphologic complexity of
the Ez -/- villi increased with postnatal age, leading to the formation
of complex amalgamated structures. The establishment and maintenance of
epithelial polarity was not affected. Saotome et al. (2004) concluded
that ezrin is not absolutely required for the formation of brush border
microvilli, but it performs a critical function in organizing the apical
domain of the intestinal epithelial cell and its associated apical
junctions.
*FIELD* RF
1. Allenspach, E. J.; Cullinan, P.; Tong, J.; Tang, Q.; Tesciuba,
A. G.; Cannon, J. L.; Takahashi, S. M.; Morgan, R.; Burkhardt, J.
K.; Sperling, A. I.: ERM-dependent movement of CD43 defines a novel
protein complex distal to the immunological synapse. Immunity 15:
739-750, 2001.
2. Bonilha, V. L.; Rodriguez-Boulan, E.: Polarity and developmental
regulation of two PDZ proteins in the retinal pigment epithelium. Invest.
Ophthal. Vis. Sci. 42: 3274-3282, 2001.
3. Faure, S.; Salazar-Fontana, L. I.; Semichon, M.; Tybulewicz, V.
L. J.; Bismuth, G.; Trautmann, A.; Germain, R. N.; Delon, J.: ERM
proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nature
Immun. 5: 272-279, 2004.
4. Gould, K. L.; Bretscher, A.; Esch, F. S.; Hunter, T.: cDNA cloning
and sequencing of the protein-tyrosine kinase substrate, ezrin, reveals
homology to band 4.1. EMBO J. 8: 4133-4142, 1989.
5. Khanna, C.; Wan, X.; Bose, S.; Cassaday, R.; Olomu, O.; Mendoza,
A.; Yeung, C.; Gorlick, R.; Hewitt, S. M.; Helman, L. J.: The membrane-cytoskeleton
linker ezrin is necessary for osteosarcoma metastasis. Nature Med. 10:
182-186, 2004.
6. Majander-Nordenswan, P.; Sainio, M.; Turunen, O.; Jaaskelainen,
J.; Carpen, O.; Kere, J.; Vaheri, A.: Genomic structure of the human
ezrin gene. Hum. Genet. 103: 662-665, 1998.
7. Mykkanen, O.-M.; Gronholm, M.; Ronty, M.; Lalowski, M. J.; Salmikangas,
P.; Suila, H.; Carpen, O.: Characterization of human palladin, a
microfilament-associated protein. Molec. Biol. Cell 12: 3060-3073,
2001.
8. Pakkanen, R.; Vaheri, A.: Cytovillin and other microvillar proteins
of human choriocarcinoma cells. J. Cell. Biochem. 41: 1-12, 1989.
9. Rao, P. H.; Murty, V. V. V. S.; Gaidano, G.; Hauptschein, R.; Dalla-Favera,
R.; Chaganti, R. S. K.: Subregional mapping of 8 single copy loci
to chromosome 6 by fluorescence in situ hybridization. Cytogenet.
Cell Genet. 66: 272-273, 1994.
10. Roumier, A.; Olivo-Marin, J. C.; Arpin, M.; Michel, F.; Martin,
M.; Mangeat, P.; Acuto, O.; Dautry-Varsat, A.; Alcover, A.: The membrane-microfilament
linker ezrin is involved in the formation of the immunological synapse
and in T cell activation. Immunity 15: 715-728, 2001.
11. Saotome, I.; Curto, M.; McClatchey, A. I.: Ezrin is essential
for epithelial organization and villus morphogenesis in the developing
intestine. Dev. Cell 6: 855-864, 2004.
12. Sharp, R.; Recio, J. A.; Jhappan, C.; Otsuka, T.; Liu, S.; Yu,
Y.; Liu, W.; Anver, M.; Navid, F.; Helman, L. J.; DePinho, R. A.;
Merlino, G.: Synergism between INK4a/ARF inactivation and aberrant
HGF/SF signaling in rhabdomyosarcomagenesis. Nature Med. 8: 1276-1280,
2002. Note: Erratum: Nature Med. 9: 146 only, 2003.
13. Spence, H. J.; Chen, Y.-J.; Batchelor, C. L.; Higginson, J. R.;
Suila, H.; Carpen, O.; Winder, S. J.: Ezrin-dependent regulation
of the actin cytoskeleton by beta-dystroglycan. Hum. Molec. Genet. 13:
1657-1668, 2004.
14. Takeda, T.; McQuistan, T.; Orlando, R. A.; Farquhar, M. G.: Loss
of glomerular foot processes is associated with uncoupling of podocalyxin
from the actin cytoskeleton. J. Clin. Invest. 108: 289-301, 2001.
15. Turunen, O.; Winqvist, R.; Pakkanen, R.; Grzeschik, K.-H.; Wahlstrom,
T.; Vaheri, A.: Cytovillin, a microvillar Mr 75,000 protein: cDNA
sequence, prokaryotic expression, and chromosomal localization. J.
Biol. Chem. 264: 16727-16732, 1989.
16. Winqvist, R.; Turunen, O.; Pakkanen, R.; Grzeschik, K.-H.: Wahlstrom,
T. and Vaheri, A.: Localization of the cytovillin gene to region q22-q27
of human chromosome 6. (Abstract) Cytogenet. Cell Genet. 51: 1108-1109,
1989.
17. Yu, Y.; Khan, J.; Khanna, C.; Helman, L.; Meltzer, P. S.; Merlino,
G.: Expression profiling identifies the cytoskeletal organizer ezrin
and the developmental homeoprotein Six-1 as key metastatic regulators. Nature
Med. 10: 175-181, 2004.
*FIELD* CN
George E. Tiller - updated: 1/16/2007
Patricia A. Hartz - updated: 10/16/2006
Patricia A. Hartz - updated: 8/10/2004
Paul J. Converse - updated: 2/13/2004
Ada Hamosh - updated: 1/30/2004
Patricia A. Hartz - updated: 9/10/2003
Jane Kelly - updated: 7/2/2002
Paul J. Converse - updated: 2/8/2002
Victor A. McKusick - updated: 1/21/1999
*FIELD* CD
Victor A. McKusick: 6/1/1989
*FIELD* ED
carol: 09/16/2013
terry: 11/28/2012
wwang: 1/22/2007
terry: 1/16/2007
mgross: 10/16/2006
mgross: 8/10/2004
alopez: 3/1/2004
alopez: 2/18/2004
alopez: 2/17/2004
mgross: 2/13/2004
alopez: 1/30/2004
carol: 10/3/2003
mgross: 9/10/2003
carol: 1/28/2003
mgross: 7/2/2002
mgross: 2/8/2002
carol: 2/1/1999
terry: 1/21/1999
alopez: 5/26/1998
jason: 6/28/1994
carol: 2/17/1993
carol: 6/3/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/11/1990
*RECORD*
*FIELD* NO
123900
*FIELD* TI
*123900 VILLIN 2; VIL2
;;CYTOVILLIN; CVIL; CVL;;
EZRIN
*FIELD* TX
DESCRIPTION
Cytovillin is a microvillar cytoplasmic peripheral membrane protein that
read moreis expressed strongly in placental syncytiotrophoblasts and in certain
human tumors. It is the same as ezrin, a component of the microvilli of
intestinal epithelial cells that serves as a major cytoplasmic substrate
for certain protein-tyrosine kinases. Ezrin, radixin (RDX; 179410), and
moesin (MSN; 309845), the so-called ERM proteins, act as linkers between
the plasma membrane and the actin cytoskeleton. They are involved in a
variety of cellular functions, such as cell adhesion, migration, and the
organization of cell surface structures. They are highly homologous,
both in protein structure and in functional activity, with
merlin/schwannomin, the NF2 tumor suppressor protein (607379).
CLONING
Winqvist et al. (1989) cloned cytovillin cDNA from a human placental
lambda gt11 library using affinity-purified antibodies. Gould et al.
(1989) cloned and sequenced a human ezrin cDNA. The deduced protein
sequence indicated that ezrin is a highly charged protein with an
overall pI of 6.1 and a calculated molecular mass of 69,000. Using the
cDNA clone to survey the distribution of the ezrin transcript, Pakkanen
and Vaheri (1989) showed that purified cytovillin reacts with antibodies
raised against ezrin. Gould et al. (1989) found the 3.2-kb ezrin mRNA in
the same tissues that are known to express the protein and at the same
relative levels. Highest expression was found in intestine, kidney, and
lung. The cDNA clone hybridized to DNAs from widely divergent organisms,
indicating that the sequence is highly conserved throughout evolution.
Within its N-terminal domain, ezrin showed a high degree of similarity
of amino acid sequence to the erythrocyte cytoskeletal protein band 4.1
(130500).
GENE FUNCTION
The immunologic synapse is the T cell-APC (antigen-presenting cell)
contact site where T-cell receptors, coreceptors, signaling molecules,
and adhesion receptors polarize upon antigen recognition. The formation
of the immunologic synapse is thought to be important for receptor
signal transduction and full T-lymphocyte activation. Using
superantigen-stimulated Jurkat cells and confocal microscopy, Roumier et
al. (2001) demonstrated that ezrin, F-actin (see ACTA1; 102610), and
CD43 (182160) relocalize to the sides, not the center, of the T cell-APC
contact area after T-cell activation, suggesting that ezrin may
contribute to setting the scaffold between the actin cytoskeleton and
transmembrane proteins facilitating cell-cell interactions and receptor
retention.
Using mouse helper T cell lines and confocal microscopy, Allenspach et
al. (2001) determined that the cytoplasmic tail of CD43 is necessary and
sufficient for CD43 removal from the immunologic synapse. In at least
some cells, CD43 is located at the distal pole of the T cell together
with ezrin and moesin. No differences in the behavior of ezrin and
moesin were noted throughout the study. Using cells from Cd43 -/- mice,
Allenspach et al. (2001) observed that ERM proteins move independently
of the large CD43 mucin. Overexpression of a dominant-negative ERM
mutant containing the N-terminal 320 amino acids of ezrin inhibited the
activation-induced movement of CD43 without affecting conjugate
formation. The dominant-negative mutant reduced cytokine production but
not the expression of T-cell activation markers.
Bonilha and Rodriguez-Boulan (2001) identified EBP50 (604990) and SAP97
(601014) as binding partners for ezrin, an actin-binding protein crucial
for morphogenesis of apical microvilli and basolateral infoldings in
retinal pigment epithelial (RPE) cells. Immunofluorescence microscopy
detected a polarized distribution of EBP50 at apical microvilli and of
SAP97 at the basolateral surface of RPE cells, which overlapped with
ezrin.
By 2-hybrid analysis, affinity precipitation, and mutation analysis,
Mykkanen et al. (2001) determined that the alpha-helical region of ezrin
interacted with the C-terminal Ig domains of the
microfilament-associated protein palladin (608092). The palladin-binding
site was masked in dormant wildtype ezrin. By double staining of ezrin
and palladin in several cell lines, Mykkanen et al. (2001) found that
the subcellular localization of ezrin differed between epithelia and
smooth muscle cells. In epithelial cells, such as HeLa, ezrin localized
at the cortical actin skeleton and demonstrated little overlap with
palladin. However, in intestinal smooth muscle cells, ezrin demonstrated
a filamentous staining pattern and partial colocalization with palladin.
Using yeast 2-hybrid analysis of a rat glomerular cDNA library, Takeda
et al. (2001) found that the PDZ-binding motif in the cytoplasmic
C-terminal tail of rat podocalyxin (PODXL; 602632) bound the second PDZ
domain of Nherf2 (SLC9A3R2; 606553). Immunocytochemical analysis
colocalized Nherf2 with podocalyxin and ezrin along the apical domain of
the glomerular epithelial cell membrane. Coimmunoprecipitation analysis
showed that Nherf2 and ezrin formed a multimeric complex with
podocalyxin. The complex interacted with the actin cytoskeleton, and
this interaction was disrupted in glomerular epithelial cells from rats
treated with agents that cause loss of foot processes. Takeda et al.
(2001) concluded that NHERF2 functions as a scaffold protein linking
podocalyxin to ezrin and the actin cytoskeleton.
Yu et al. (2004) established highly and poorly metastatic
rhabdomyosarcoma cell lines derived from a transgenic mouse model
overexpressing Hgf/Sf (142409) and deficient for Ink4a/Arf (600160), in
which skeletal muscle tumors reminiscent of those in embryonic
rhabdomyosarcoma (268210) arise with very high penetrance and short
latency (Sharp et al., 2002). Yu et al. (2004) then used cDNA microarray
analysis of these cell lines to identify a set of genes whose expression
was significantly different between highly and poorly metastatic cells.
Subsequent in vivo functional studies revealed that ezrin and Six1
(601205) have essential roles in determining the metastatic fate of
rhabdomyosarcoma cells. VIL2 and SIX1 expression was enhanced in human
rhabdomyosarcoma tissue, significantly correlating with clinical stage.
By imaging osteosarcoma cells in the lungs of mice, Khanna et al. (2004)
showed that ezrin expression provides an early survival advantage for
cancer cells that reach the lung. AKT (164730) and MAPK3 (601795)
phosphorylation and activity were reduced when ezrin was suppressed.
Ezrin-mediated early metastatic survival was partially dependent on the
activation of MAPK but not AKT. To define the relevance of ezrin in the
biology of metastasis beyond the founding mouse model, Khanna et al.
(2004) examined ezrin expression in dogs that naturally developed
osteosarcoma. High ezrin expression in dog tumors was associated with
early development of metastases. Consistent with these data, Khanna et
al. (2004) found a significant association between high ezrin expression
and poor outcome in pediatric osteosarcoma patients.
Using antigen-activated T cells, Faure et al. (2004) showed that the ERM
proteins are rapidly inactivated through a VAV1 (164875)-RAC1 (602048)
pathway. The resulting disanchoring of the cortical actin cytoskeleton
from the plasma membrane decreased cellular rigidity, leading to more
efficient T cell-APC conjugate formation. The authors concluded that
this pathway favors immunologic synapse formation and the development of
an effective immune response.
Dystroglycan (DAG1; 128239) is part of an adhesion receptor complex
linking the extracellular matrix to the actin cytoskeleton. Spence et
al. (2004) localized beta-dystroglycan to microvilli structures in a
number of cell types where it associated with ezrin, through which it
was able to modulate the actin cytoskeleton and induced peripheral
filopodia and microvilli. Ezrin was able to interact with dystroglycan
through a cluster of basic residues in the juxtamembrane region of
dystroglycan, and mutation of these residues both prevented ezrin
binding and the induction of actin-rich surface protrusions.
GENE STRUCTURE
Majander-Nordenswan et al. (1998) reported the genomic structure and
intron junction sequences of the human ezrin gene. The gene consists of
13 exons and spans approximately 24 kb of genomic DNA. The exons range
in size from 12 bp to 275 bp and the introns from 182 bp to 7 kb. The
genomic structures of ezrin and moesin are highly conserved, suggesting
that they diverged recently.
MAPPING
By Southern blotting of panels of human-mouse somatic cell hybrids,
Turunen et al. (1989) localized the VIL2 gene to 6q22-q27 (or perhaps
6q25-q27). Since the VIL2 gene was not coamplified with the MYB gene
(189990) in colon cancer cell lines, it is probably not located close to
the MYB gene at 6q22-q23. By fluorescence in situ hybridization, Rao et
al. (1994) mapped the VIL2 gene to 6q25-q26. By radiation hybrid
mapping, Majander-Nordenswan et al. (1998) refined the location of the
ezrin gene to the interval between D6S442 and D6S281.
ANIMAL MODEL
Saotome et al. (2004) created mice with a conditional mutation in the
ezrin gene. Homozygous mutant mice were born at submendelian ratios
(about 12%). Despite their normal appearance at birth, they failed to
thrive and did not survive past weaning. The luminal surface of Ez -/-
intestine was covered with cauliflower-shaped villi that appeared to be
aggregates of multiple individual villi. The morphologic complexity of
the Ez -/- villi increased with postnatal age, leading to the formation
of complex amalgamated structures. The establishment and maintenance of
epithelial polarity was not affected. Saotome et al. (2004) concluded
that ezrin is not absolutely required for the formation of brush border
microvilli, but it performs a critical function in organizing the apical
domain of the intestinal epithelial cell and its associated apical
junctions.
*FIELD* RF
1. Allenspach, E. J.; Cullinan, P.; Tong, J.; Tang, Q.; Tesciuba,
A. G.; Cannon, J. L.; Takahashi, S. M.; Morgan, R.; Burkhardt, J.
K.; Sperling, A. I.: ERM-dependent movement of CD43 defines a novel
protein complex distal to the immunological synapse. Immunity 15:
739-750, 2001.
2. Bonilha, V. L.; Rodriguez-Boulan, E.: Polarity and developmental
regulation of two PDZ proteins in the retinal pigment epithelium. Invest.
Ophthal. Vis. Sci. 42: 3274-3282, 2001.
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*FIELD* CN
George E. Tiller - updated: 1/16/2007
Patricia A. Hartz - updated: 10/16/2006
Patricia A. Hartz - updated: 8/10/2004
Paul J. Converse - updated: 2/13/2004
Ada Hamosh - updated: 1/30/2004
Patricia A. Hartz - updated: 9/10/2003
Jane Kelly - updated: 7/2/2002
Paul J. Converse - updated: 2/8/2002
Victor A. McKusick - updated: 1/21/1999
*FIELD* CD
Victor A. McKusick: 6/1/1989
*FIELD* ED
carol: 09/16/2013
terry: 11/28/2012
wwang: 1/22/2007
terry: 1/16/2007
mgross: 10/16/2006
mgross: 8/10/2004
alopez: 3/1/2004
alopez: 2/18/2004
alopez: 2/17/2004
mgross: 2/13/2004
alopez: 1/30/2004
carol: 10/3/2003
mgross: 9/10/2003
carol: 1/28/2003
mgross: 7/2/2002
mgross: 2/8/2002
carol: 2/1/1999
terry: 1/21/1999
alopez: 5/26/1998
jason: 6/28/1994
carol: 2/17/1993
carol: 6/3/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/11/1990