WWTR1_MOUSE
ID WWTR1_MOUSE Reviewed; 395 AA.
AC Q9EPK5; Q3UQ69; Q3UQM0; Q99KI4;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2005, sequence version 2.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=WW domain-containing transcription regulator protein 1;
DE AltName: Full=Transcriptional coactivator with PDZ-binding motif;
GN Name=Wwtr1; Synonyms=Taz;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP INTERACTION WITH SLC9A3R2 AND YWHAZ, PHOSPHORYLATION AT SER-89, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF SER-89 AND 392-GLU--LEU-395.
RX PubMed=11118213; DOI=10.1093/emboj/19.24.6778;
RA Kanai F., Marignani P.A., Sarbassova D., Yagi R., Hall R.A., Donowitz M.,
RA Hisaminato A., Fujiwara T., Ito Y., Cantley L.C., Yaffe M.B.;
RT "TAZ: a novel transcriptional co-activator regulated by interactions with
RT 14-3-3 and PDZ domain proteins.";
RL EMBO J. 19:6778-6791(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J; TISSUE=Heart;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N; TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-89, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, and Lung;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION, INTERACTION WITH PALS1; LATS1 AND YAP1, AND SUBCELLULAR LOCATION.
RX PubMed=21145499; DOI=10.1016/j.devcel.2010.11.012;
RA Varelas X., Samavarchi-Tehrani P., Narimatsu M., Weiss A., Cockburn K.,
RA Larsen B.G., Rossant J., Wrana J.L.;
RT "The Crumbs complex couples cell density sensing to Hippo-dependent control
RT of the TGF-beta-SMAD pathway.";
RL Dev. Cell 19:831-844(2010).
CC -!- FUNCTION: Transcriptional coactivator which acts as a downstream
CC regulatory target in the Hippo signaling pathway that plays a pivotal
CC role in organ size control and tumor suppression by restricting
CC proliferation and promoting apoptosis (PubMed:11118213). The core of
CC this pathway is composed of a kinase cascade wherein STK3/MST2 and
CC STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates
CC and activates LATS1/2 in complex with its regulatory protein MOB1,
CC which in turn phosphorylates and inactivates YAP1 oncoprotein and
CC WWTR1/TAZ (By similarity). WWTR1 enhances PAX8 and NKX2-1/TTF1-
CC dependent gene activation (By similarity). In conjunction with YAP1,
CC involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear
CC accumulation (PubMed:21145499). Plays a key role in coupling SMADs to
CC the transcriptional machinery such as the mediator complex (By
CC similarity). Regulates embryonic stem-cell self-renewal, promotes cell
CC proliferation and epithelial-mesenchymal transition (By similarity).
CC {ECO:0000250|UniProtKB:Q9GZV5, ECO:0000269|PubMed:11118213,
CC ECO:0000269|PubMed:21145499}.
CC -!- SUBUNIT: Binds to SLC9A3R2 via the PDZ motif at the plasma membrane
CC (PubMed:11118213). Binds to YWHAZ in vivo and in vitro through the
CC phosphoserine-binding motif RSHSSP (PubMed:11118213). Interacts (via
CC coiled-coil domain) with SMAD2 (via MH1 domain), SMAD3 and SMAD4 (By
CC similarity). Interacts with MED15 (By similarity). Interacts with PAX8
CC and NKX2-1 (By similarity). Interacts with TEAD1, TEAD2, TEAD3 and
CC TEAD4 (By similarity). Interacts (via WW domain) with PALS1
CC (PubMed:21145499). Interacts with LATS1 (PubMed:21145499). Interacts
CC with YAP1 (when phosphorylated at 'Ser-112') (PubMed:21145499).
CC Interacts (via WW domain) with PRRG4 (via cytoplasmic domain) (By
CC similarity). {ECO:0000250|UniProtKB:Q9GZV5,
CC ECO:0000269|PubMed:11118213, ECO:0000269|PubMed:21145499}.
CC -!- INTERACTION:
CC Q9EPK5; O35625: Axin1; NbExp=4; IntAct=EBI-1211920, EBI-2365912;
CC Q9EPK5; Q8IX12: CCAR1; Xeno; NbExp=5; IntAct=EBI-1211920, EBI-356265;
CC Q9EPK5; P35222: CTNNB1; Xeno; NbExp=2; IntAct=EBI-1211920, EBI-491549;
CC Q9EPK5; P23441: Nkx2-1; Xeno; NbExp=3; IntAct=EBI-1211920, EBI-1223127;
CC Q9EPK5; Q07157: TJP1; Xeno; NbExp=4; IntAct=EBI-1211920, EBI-79553;
CC Q9EPK5; Q95168: TJP2; Xeno; NbExp=4; IntAct=EBI-1211920, EBI-8304003;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11118213,
CC ECO:0000269|PubMed:21145499}. Cytoplasm {ECO:0000269|PubMed:11118213,
CC ECO:0000269|PubMed:21145499}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9GZV5}. Note=Concentrates along specific
CC portions of the plasma membrane, and accumulates in punctate nuclear
CC bodies (PubMed:11118213). When phosphorylated is retained in the
CC cytoplasm by YWHAZ (PubMed:11118213). Can be retained in the nucleus by
CC MED15 (By similarity). Localized in the cytoplasm in areas of
CC epithelial cell high density (PubMed:21145499). At blastocyst stage
CC expressed in the nucleus in trophectodermal cells, however expressed in
CC the cytoplasm in the inner cell mass (PubMed:21145499).
CC {ECO:0000250|UniProtKB:Q9GZV5, ECO:0000269|PubMed:11118213,
CC ECO:0000269|PubMed:21145499}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9EPK5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9EPK5-2; Sequence=VSP_026137;
CC -!- TISSUE SPECIFICITY: Highly expressed in kidney, heart, placenta and
CC lung. {ECO:0000269|PubMed:11118213}.
CC -!- DOMAIN: The PDZ-binding motif is essential for stimulated gene
CC transcription. It localizes the protein into both punctate nuclear foci
CC and plasma membrane-associated complexes.
CC -!- DOMAIN: Binds to transcription factors via its WW domain.
CC -!- PTM: Phosphorylated by LATS2 and STK3/MST2. Phosphorylation by LATS2
CC results in creation of 14-3-3 binding sites, retention in the
CC cytoplasm, and functional inactivation (By similarity). Phosphorylation
CC results in the inhibition of transcriptional coactivation through
CC YWHAZ-mediated nuclear export. {ECO:0000250,
CC ECO:0000269|PubMed:11118213}.
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DR EMBL; AJ299430; CAC17733.1; -; mRNA.
DR EMBL; AK142299; BAE25019.1; -; mRNA.
DR EMBL; AK142720; BAE25174.1; -; mRNA.
DR EMBL; BC004640; AAH04640.1; -; mRNA.
DR EMBL; BC014727; AAH14727.1; -; mRNA.
DR CCDS; CCDS38434.1; -. [Q9EPK5-1]
DR CCDS; CCDS50912.1; -. [Q9EPK5-2]
DR RefSeq; NP_001161753.1; NM_001168281.1. [Q9EPK5-2]
DR RefSeq; NP_598545.2; NM_133784.3. [Q9EPK5-1]
DR PDB; 5GN0; X-ray; 2.90 A; E/F/G/H=24-57.
DR PDBsum; 5GN0; -.
DR AlphaFoldDB; Q9EPK5; -.
DR SMR; Q9EPK5; -.
DR BioGRID; 220584; 61.
DR CORUM; Q9EPK5; -.
DR DIP; DIP-39476N; -.
DR ELM; Q9EPK5; -.
DR IntAct; Q9EPK5; 24.
DR MINT; Q9EPK5; -.
DR STRING; 10090.ENSMUSP00000113040; -.
DR iPTMnet; Q9EPK5; -.
DR PhosphoSitePlus; Q9EPK5; -.
DR MaxQB; Q9EPK5; -.
DR PaxDb; Q9EPK5; -.
DR PeptideAtlas; Q9EPK5; -.
DR PRIDE; Q9EPK5; -.
DR ProteomicsDB; 299777; -. [Q9EPK5-1]
DR ProteomicsDB; 299778; -. [Q9EPK5-2]
DR Antibodypedia; 1743; 377 antibodies from 36 providers.
DR DNASU; 97064; -.
DR Ensembl; ENSMUST00000029380; ENSMUSP00000029380; ENSMUSG00000027803. [Q9EPK5-1]
DR Ensembl; ENSMUST00000120977; ENSMUSP00000113040; ENSMUSG00000027803. [Q9EPK5-2]
DR GeneID; 97064; -.
DR KEGG; mmu:97064; -.
DR UCSC; uc008phb.2; mouse. [Q9EPK5-1]
DR UCSC; uc012cpt.1; mouse. [Q9EPK5-2]
DR CTD; 25937; -.
DR MGI; MGI:1917649; Wwtr1.
DR VEuPathDB; HostDB:ENSMUSG00000027803; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00510000046760; -.
DR HOGENOM; CLU_041917_0_0_1; -.
DR InParanoid; Q9EPK5; -.
DR OMA; AVNTPAM; -.
DR OrthoDB; 1006566at2759; -.
DR PhylomeDB; Q9EPK5; -.
DR TreeFam; TF326941; -.
DR Reactome; R-MMU-2028269; Signaling by Hippo.
DR Reactome; R-MMU-2032785; YAP1- and WWTR1 (TAZ)-stimulated gene expression.
DR Reactome; R-MMU-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
DR BioGRID-ORCS; 97064; 10 hits in 75 CRISPR screens.
DR ChiTaRS; Wwtr1; mouse.
DR PRO; PR:Q9EPK5; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q9EPK5; protein.
DR Bgee; ENSMUSG00000027803; Expressed in left lung lobe and 251 other tissues.
DR Genevisible; Q9EPK5; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005667; C:transcription regulator complex; IDA:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0003714; F:transcription corepressor activity; IGI:MGI.
DR GO; GO:0060271; P:cilium assembly; IMP:MGI.
DR GO; GO:0032835; P:glomerulus development; IMP:MGI.
DR GO; GO:0003015; P:heart process; IMP:ARUK-UCL.
DR GO; GO:0035329; P:hippo signaling; ISO:MGI.
DR GO; GO:0060993; P:kidney morphogenesis; IMP:MGI.
DR GO; GO:0048762; P:mesenchymal cell differentiation; IMP:MGI.
DR GO; GO:0035264; P:multicellular organism growth; IMP:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IGI:MGI.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; ISO:MGI.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0001649; P:osteoblast differentiation; IMP:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISO:MGI.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; ISO:MGI.
DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0016567; P:protein ubiquitination; IDA:MGI.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; IGI:MGI.
DR GO; GO:0072307; P:regulation of metanephric nephron tubule epithelial cell differentiation; IGI:MGI.
DR GO; GO:0060390; P:regulation of SMAD protein signal transduction; ISO:MGI.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IMP:MGI.
DR GO; GO:0017145; P:stem cell division; ISO:MGI.
DR GO; GO:0001894; P:tissue homeostasis; IMP:ARUK-UCL.
DR CDD; cd00201; WW; 1.
DR InterPro; IPR001202; WW_dom.
DR InterPro; IPR036020; WW_dom_sf.
DR Pfam; PF00397; WW; 1.
DR SMART; SM00456; WW; 1.
DR SUPFAM; SSF51045; SSF51045; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 1.
DR PROSITE; PS50020; WW_DOMAIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Cell membrane; Coiled coil;
KW Cytoplasm; Membrane; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation.
FT CHAIN 1..395
FT /note="WW domain-containing transcription regulator protein
FT 1"
FT /id="PRO_0000076070"
FT DOMAIN 124..157
FT /note="WW"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT REGION 52..116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 221..395
FT /note="Required for interaction with PALS1"
FT /evidence="ECO:0000250|UniProtKB:Q9GZV5"
FT REGION 277..308
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 224..258
FT /evidence="ECO:0000255"
FT MOTIF 389..395
FT /note="PDZ-binding"
FT /evidence="ECO:0000250"
FT COMPBIAS 58..72
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 62
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZV5"
FT MOD_RES 89
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 89
FT /note="Phosphoserine; by LATS2"
FT /evidence="ECO:0000250"
FT MOD_RES 290
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZV5"
FT MOD_RES 306
FT /note="Phosphoserine; by LATS2"
FT /evidence="ECO:0000250|UniProtKB:Q9GZV5"
FT VAR_SEQ 1
FT /note="M -> MHNSTAPLSARLFPKGGSLLQTLFMGQSGSRGGCARLRLLCRLLAQW
FT ERPRPVPGIKM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_026137"
FT MUTAGEN 89
FT /note="S->A: Loss of YWHAZ binding with increased nuclear
FT localization. Partial recovery of nuclear accumulation;
FT when associated with deletion of 392-L--L-395."
FT /evidence="ECO:0000269|PubMed:11118213"
FT MUTAGEN 392..395
FT /note="Missing: Loss of SLC9A3R2 binding and reduced
FT nuclear localization. Partial recovery of nuclear
FT accumulation; when associated with A-89."
FT /evidence="ECO:0000269|PubMed:11118213"
FT CONFLICT 384
FT /note="A -> V (in Ref. 1; CAC17733)"
FT /evidence="ECO:0000305"
FT HELIX 29..31
FT /evidence="ECO:0007829|PDB:5GN0"
FT HELIX 43..45
FT /evidence="ECO:0007829|PDB:5GN0"
FT HELIX 50..52
FT /evidence="ECO:0007829|PDB:5GN0"
SQ SEQUENCE 395 AA; 43620 MW; 1B8A7487D4CA341C CRC64;
MNPSSVPHPL PPPGQQVIHV TQDLDTDLEA LFNSVMNPKP SSWRKKILPE SFFKEPDSGS
HSRQSSTDSS GGHPGPRLAG GAQHVRSHSS PASLQLGTGA GAAGGPAQQH AHLRQQSYDV
TDELPLPPGW EMTFTATGQR YFLNHIEKIT TWQDPRKVMN QPLNHVNLHP SITSTSVPQR
SMAVSQPNLA MNHQHQQVVA TSLSPQNHPT QNQPTGLMSV PNALTTQQQQ QQKLRLQRIQ
MERERIRMRQ EELMRQEAAL CRQLPMETET MAPVNTPAMS TDMRSVTNSS SDPFLNGGPY
HSREQSTDSG LGLGCYSVPT TPEDFLSNMD EMDTGENSGQ TPMTVNPQQT RFPDFLDCLP
GTNVDLGTLE SEDLIPLFND VESALNKSEP FLTWL
