Q9EPK5 (WWTR1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
WW domain-containing transcription regulator protein 1

Alternative name(s):
Transcriptional coactivator with PDZ-binding motif

Gene names

Name:	Wwtr1
Synonyms:	Taz

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	395 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. Regulates the nuclear accumulation of SMADS and has a key role in coupling them to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition By similarity. Ref.1
Subunit structure	Binds to SLC9A3R2 via the PDZ motif at the plasma membrane. Binds to YWHAZ in vivo and in vitro through the phosphoserine-binding motif RSHSSP. Interacts (via coiled-coil domain) with SMAD2 (via MH1 domain), SMAD3 and SMAD4. Interacts with MED15, PAX8 and NKX2-1. Interacts with TEAD1, TEAD2, TEAD3 and TEAD4 By similarity. Ref.1
Subcellular location	Nucleus. Cytoplasm. Note: Concentrates along specific portions of the plasma membrane, and accumulates in punctate nuclear bodies. When phosphorylated is retained in cytoplasm by YWHAZ. Can be retained in the nucleus by MED15 By similarity. Ref.1
Tissue specificity	Highly expressed in kidney, heart, placenta and lung. Ref.1
Domain	The PDZ-binding motif is essential for stimulated gene transcription. It localizes the protein into both punctate nuclear foci and plasma membrane-associated complexes. Binds to transcription factors via its WW domain.
Post-translational modification	Phosphorylated by LATS2 and STK3/MST2. Phosphorylation by LATS2 results in creation of 14-3-3 binding sites, retention in the cytoplasm, and functional inactivation By similarity. Phosphorylation results in the inhibition of transcriptional coactivation through YWHAZ-mediated nuclear export. Ref.1
Sequence similarities	Contains 1 WW domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Coiled coil
Molecular function	Activator
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cilium morphogenesis Inferred from mutant phenotype PubMed 17251353. Source: MGI glomerulus development Inferred from mutant phenotype PubMed 18172001. Source: MGI hippo signaling cascade Inferred from electronic annotation. Source: Compara negative regulation of canonical Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of catenin import into nucleus Inferred from electronic annotation. Source: Compara negative regulation of fat cell differentiation Inferred from genetic interaction PubMed 16099986. Source: MGI negative regulation of protein kinase activity Inferred from electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Inferred from genetic interaction PubMed 16099986. Source: MGI osteoblast differentiation Inferred from mutant phenotype PubMed 16099986. Source: MGI positive regulation of cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of epithelial to mesenchymal transition Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 14970209. Source: MGI regulation of SMAD protein import into nucleus Inferred from electronic annotation. Source: Compara stem cell division Inferred from electronic annotation. Source: Compara transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasm Inferred from direct assay Ref.1PubMed 16099986. Source: MGI transcription factor complex Inferred from direct assay PubMed 14970209. Source: MGI
Molecular_function	protein homodimerization activity Inferred from direct assay PubMed 16332960. Source: UniProtKB transcription coactivator activity Inferred from direct assay PubMed 16332960. Source: UniProtKB transcription corepressor activity Inferred from genetic interaction PubMed 16099986. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCAR1	Q8IX12	5	EBI-1211920,EBI-356265	From a different organism.
CTNNB1	P35222	2	EBI-1211920,EBI-491549	From a different organism.
Nkx2-1	P23441	3	EBI-1211920,EBI-1223127	From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9EPK5-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9EPK5-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MHNSTAPLSARLFPKGGSLLQTLFMGQSGSRGGCARLRLLCRLLAQWERPRPVPGIKM

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 395	395	WW domain-containing transcription regulator protein 1		PRO_0000076070
Regions
	Domain	124 – 157	34	WW
	Coiled coil	224 – 258	35	Potential
	Motif	389 – 395	7	PDZ-binding By similarity
Amino acid modifications
	Modified residue	89	1	Phosphoserine; by LATS2 By similarity
	Modified residue	93	1	Phosphoserine Ref.4
	Modified residue	306	1	Phosphoserine; by LATS2 By similarity
Natural variations
	Alternative sequence	1	1	M → MHNSTAPLSARLFPKGGSLL QTLFMGQSGSRGGCARLRLL CRLLAQWERPRPVPGIKM in isoform 2.		VSP_026137
Experimental info
	Mutagenesis	89	1	S → A: Loss of YWHAZ binding with increased nuclear localization. Partial recovery of nuclear accumulation; when associated with deletion of 392-L--L-395. Ref.1
	Mutagenesis	392 – 395	4	Missing: Loss of SLC9A3R2 binding and reduced nuclear localization. Partial recovery of nuclear accumulation; when associated with A-89. Ref.1
	Sequence conflict	384	1	A → V in CAC17733. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 7, 2005. Version 2. Checksum: 1B8A7487D4CA341C	FASTA	395	43,620
	10 20 30 40 50 60 MNPSSVPHPL PPPGQQVIHV TQDLDTDLEA LFNSVMNPKP SSWRKKILPE SFFKEPDSGS 70 80 90 100 110 120 HSRQSSTDSS GGHPGPRLAG GAQHVRSHSS PASLQLGTGA GAAGGPAQQH AHLRQQSYDV 130 140 150 160 170 180 TDELPLPPGW EMTFTATGQR YFLNHIEKIT TWQDPRKVMN QPLNHVNLHP SITSTSVPQR 190 200 210 220 230 240 SMAVSQPNLA MNHQHQQVVA TSLSPQNHPT QNQPTGLMSV PNALTTQQQQ QQKLRLQRIQ 250 260 270 280 290 300 MERERIRMRQ EELMRQEAAL CRQLPMETET MAPVNTPAMS TDMRSVTNSS SDPFLNGGPY 310 320 330 340 350 360 HSREQSTDSG LGLGCYSVPT TPEDFLSNMD EMDTGENSGQ TPMTVNPQQT RFPDFLDCLP 370 380 390 GTNVDLGTLE SEDLIPLFND VESALNKSEP FLTWL
	Isoform 2 [UniParc]. Checksum: 6A8D7114823BA29F	FASTA	452	49,834
	10 20 30 40 50 60 MHNSTAPLSA RLFPKGGSLL QTLFMGQSGS RGGCARLRLL CRLLAQWERP RPVPGIKMNP 70 80 90 100 110 120 SSVPHPLPPP GQQVIHVTQD LDTDLEALFN SVMNPKPSSW RKKILPESFF KEPDSGSHSR 130 140 150 160 170 180 QSSTDSSGGH PGPRLAGGAQ HVRSHSSPAS LQLGTGAGAA GGPAQQHAHL RQQSYDVTDE 190 200 210 220 230 240 LPLPPGWEMT FTATGQRYFL NHIEKITTWQ DPRKVMNQPL NHVNLHPSIT STSVPQRSMA 250 260 270 280 290 300 VSQPNLAMNH QHQQVVATSL SPQNHPTQNQ PTGLMSVPNA LTTQQQQQQK LRLQRIQMER 310 320 330 340 350 360 ERIRMRQEEL MRQEAALCRQ LPMETETMAP VNTPAMSTDM RSVTNSSSDP FLNGGPYHSR 370 380 390 400 410 420 EQSTDSGLGL GCYSVPTTPE DFLSNMDEMD TGENSGQTPM TVNPQQTRFP DFLDCLPGTN 430 440 450 VDLGTLESED LIPLFNDVES ALNKSEPFLT WL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins." Kanai F., Marignani P.A., Sarbassova D., Yagi R., Hall R.A., Donowitz M., Hisaminato A., Fujiwara T., Ito Y., Cantley L.C., Yaffe M.B. EMBO J. 19:6778-6791(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SLC9A3R2 AND YWHAZ, PHOSPHORYLATION AT SER-89, TISSUE SPECIFICITY, MUTAGENESIS OF SER-89 AND 392-GLU--LEU-395.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Strain: C57BL/6J. Tissue: Heart.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Strain: FVB/N. Tissue: Mammary tumor.
[4]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-93, MASS SPECTROMETRY. Tissue: Liver.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ299430 mRNA. Translation: CAC17733.1. AK142299 mRNA. Translation: BAE25019.1. AK142720 mRNA. Translation: BAE25174.1. BC004640 mRNA. Translation: AAH04640.1. BC014727 mRNA. Translation: AAH14727.1.
IPI	IPI00320121. IPI00848891.
RefSeq	NP_001161753.1. NM_001168281.1. NP_598545.2. NM_133784.3.
UniGene	Mm.405029.
3D structure databases
ProteinModelPortal	Q9EPK5.
SMR	Q9EPK5. Positions 14-57, 123-157.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9EPK5. 9 interactions.
MINT	MINT-4123841.
PTM databases
PhosphoSite	Q9EPK5.
Proteomic databases
PaxDb	Q9EPK5.
PRIDE	Q9EPK5.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000029380; ENSMUSP00000029380; ENSMUSG00000027803. ENSMUST00000120977; ENSMUSP00000113040; ENSMUSG00000027803.
GeneID	97064.
KEGG	mmu:97064.
UCSC	uc008phb.2. mouse. uc012cpt.1. mouse.
Organism-specific databases
CTD	25937.
MGI	MGI:1917649. Wwtr1.
Phylogenomic databases
eggNOG	NOG247722.
GeneTree	ENSGT00510000046760.
HOGENOM	HOG000007854.
HOVERGEN	HBG002748.
InParanoid	Q9EPK5.
KO	K16820.
OMA	MAMSQPN.
OrthoDB	EOG4MSCZC.
Enzyme and pathway databases
Reactome	REACT_78136. Gene Expression.
Gene expression databases
Bgee	Q9EPK5.
CleanEx	MM_WWTR1.
Genevestigator	Q9EPK5.
GermOnline	ENSMUSG00000027803. Mus musculus.
Family and domain databases
InterPro	IPR001202. WW_dom. [Graphical view]
Pfam	PF00397. WW. 1 hit. [Graphical view]
SMART	SM00456. WW. 1 hit. [Graphical view]
SUPFAM	SSF51045. WW_Rsp5_WWP. 1 hit.
PROSITE	PS01159. WW_DOMAIN_1. 1 hit. PS50020. WW_DOMAIN_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	352477.
SOURCE	Search...

Entry information

Entry name

WWTR1_MOUSE

Accession

Primary (citable) accession number: Q9EPK5
Secondary accession number(s): Q3UQ69, Q3UQM0, Q99KI4

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 7, 2005
Last sequence update:	June 7, 2005
Last modified:	May 29, 2013
This is version 91 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program