WWTR1 (WW domain containing transcription regulator 1)

2014-03-01   Yulei Zhao , Xiaolong Yang 

Department of Pathology, Molecular Medicine, Queens University, Kingston, ON, Canada




WWTR1 (also called TAZ in publications. Therefore, TAZ is used in the following description) is a WW domaing-containing transcriptional coactivator, which was first identified as a 14-3-3 binding protein. TAZ is the downstream component in the Hippo pathway, and also has been found to interact with different pathways, such as Wnt, TGFbeta, etc. TAZ is involved in mesenchymal stem cell differentiation as well as tumorigenesis. High level of TAZ has been found in different cancers, such as breast cancer, colon cancer, lung cancer, etc.



TAZ maps to NC_000003.12, in the region between 149235022 to 149454501 and spans 220 kilobases. TAZ has 7 exons, ranging in size from 112 bp to 3754 bp.


The mRNA transcript spans 5135 bp with 1202 bp open reading frame.


Atlas Image
TAZ structure domain. TB: TEAD binding domain; WW: WW domain; TA: Transactivation domain, which contains a Gln-rich region (194-241 aa) and Coiled-coil region (225-259 aa); PDZB: PDZ-binding domain; S89-LATS phosphorylation site.


TAZ is a downstream transcriptional coactivator in the Hippo pathway (Kanai et al., 2000; Lei et al., 2008; Hong and Guan, 2012). TAZ has one WW domain which allows its interaction with PPxY motif-containing proteins such as LATS kinases in the Hippo pathway as well as other transcription factors (TFs). Its N-termini contains a Tead-binding (TB) domain, through which TAZ can bind to TEAD, which is a well-known TF involved in cell proliferation and anti-apoptosis. In its C-termini, there is a Transcriptional Activation (TA) domain which contains a Gln-rich region (amino acid (aa.) 194-241) and Coiled-coil region (aa. 225-259). From 394 to aa. 400 of TAZ, there is a PDZ-binding domain, which has been found important for transcriptional coactivating function of TAZ (Wang et al., 2009; Liu et al., 2011).


TAZ is expressed in various tissues, and high expression of TAZ has been found in thyroid, kidney, heart, placenta and lung.


TAZ localizes in both cytoplasm and nucleus. Normally, in the nucleus, TAZ can possess its transcription-activating function and help initiate target genes expressions through binding with related transcriptional factors. And the localization of TAZ can be regulated by cell-cell contact. Once cells get confluent (high cell-cell contact), the Hippo pathway will be activated (Zhao et al., 2011). As a result, TAZ will be phosphorylated on S89, initiating its binding with 14-3-3 (Lei et al., 2008; Zhao et al., 2008), which will anchor TAZ in the cytoplasm. Besides, the interaction with some proteins, such as AMOT and ZO-1, can also localize TAZ to cell membrane (Chan et al., 2011; Remue et al., 2010).


TAZ functions as an oncogene. Over-expression of TAZ induces increased cell proliferation, epithelial-mesenchymal transition (EMT), cell migration and transformation (Chan et al., 2009; Lai et al., 2011). In addition, enhanced levels of TAZ causes drug resistance by activating CTGF and Cyr61 (Lai et al., 2011).
TAZ is also involved in mesenchymal stem cell differentiation. TAZ can activate TF RUNX2 to induce osteoblast differentiation, while TAZ binds and inhibits PPARG TF, which further blocks adipocyte differentiation. Besides, TAZ also regulates myoblast differentiation by enhancing TF MyoD-dependent myogenic gene expression (Hong et al., 2005; Jung et al., 2009; Cho HH et al., 2010).
TAZ relates to tissue homeostasis and development as well. TAZ knockout mice develop Polycystic Kidney Disease (PKD) and emphysema, suggesting an important role of TAZ in renal and lung development (Liu et al., 2011).
TAZ also plays a role in mechanotransduction. Extracellular matrix stiffness or confined adhesiveness can cause TAZ retention in nuclear, which, therefore contributes to cell proliferation, mesenchymal stem cell differentiation as well as cancer malignant progression (Dupont et al., 2011).


TAZ gene is conserved across species. Homologous proteins have been found in chimpanzee, dog, cow, mouse, rate, chicken and zebrafish.



TAZ has a missense mutation (F299V), which was detected at 7% and 10% in primary mammary tumor and xenograft respectively, as well as 28% mutant allele frequency in metastatic breast cancers (Ding et al., 2010).

Implicated in

Entity name
Non-small cell lung cancer
High level of TAZ has been found in different non-small cell lung cancer (NSCLC) cell lines. TAZ overexpression in immortalized non-tumorigenic lung epithelial cells causes increased cell proliferation and transformation, whereas TAZ knockdown in NSCLC cells significantly reduces tumor cell proliferation and tumor growth in nude mice (Zhou et al., 2011). Significantly, TAZ expression was found associated with lung adenocarcinoma, metastasis, poorer differentiation and poor prognosis (Xie et al., 2012). Lung cancer patients with negative TAZ expression have prolonged overall survival (Lau et al., 2014).
Entity name
Colorectal cancer
High levels of TAZ mRNA are significantly correlated with shorter survival in colorectal cancer patients. This was due to the increased levels of TAZ downstream target genes CTGF and AXL, which are involved in colorectal cancer development (Yuen et al., 2013).
Entity name
Breast cancer
TAZ has been found correlated with breast cancers. The breast cancer cell lines have high expression of TAZ and 20% of breast cancer samples have TAZ overexpression (Chan et al., 2009). TAZ causes increased cell migration through activation of BMP4, and resistance to chemotherapeutic drug Taxol through downstream Cyr61 and CTGF (Lai et al., 2011; Lai and Yang, 2013). TAZ can also cause increased cell proliferation and tumorigenesis by activating KLF5 through inhibition of KLF5 degradation (Zhao et al., 2012). Also, TAZ has been suggested to play a role in breast cancer stem cell self-renewal and tumor-initiation capabilities (Cordenonsi et al., 2011; Bartucci et al., 2014). Moreover, TAZ is also found amplified in 44% basal-like and 30% luminal breast cancer (Skibinski et al., 2014).
Entity name
Tongue squamous cell carcinoma (TSCC)
TSCC cells and specimens have significantly higher expression of TAZ than those in non-cancerous cells and normal tongue mucosa. Overexpression of TAZ in TSCC was significantly associated with tumor size, clinical stage and reduced overall and disease-free survival (Wei et al., 2013).
Entity name
Polycystic kidney disease (PKD)
TAZ knockout mice develop PKD during development. NEK1 kinase can phosphorylate TAZ, which can disable TAZs role in promoting the degradation of PC2, a protein involved in ciliogenesis. The proper balance of NEK1 and TAZ will help keep a good level of PC2, which will protect kidney from PKD (Tian et al., 2007; Yim et al., 2011).
Entity name
Holt-Oram syndrome
TAZ can interact with and activate transcription factor TBX5, which is essential in cardiac and limb development. In Holt-Oram syndrome, TBX5 has a truncated mutation, which will lose its interaction with TAZ and therefore, fail to activate genes involved in cardiac and limb development (Murakami et al., 2005).


Pubmed IDLast YearTitleAuthors
245317102015TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.Bartucci M et al
212243872011Hippo pathway-independent restriction of TAZ and YAP by angiomotin.Chan SW et al
200498722010NF-kappaB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression.Cho HH et al
220788772011The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.Cordenonsi M et al
203935552010Genome remodelling in a basal-like breast cancer metastasis and xenograft.Ding L et al
216547992011Role of YAP/TAZ in mechanotransduction.Dupont S et al
160999862005TAZ, a transcriptional modulator of mesenchymal stem cell differentiation.Hong JH et al
226594962012The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway.Hong W et al
195918062009Augmentation of PPARgamma-TAZ interaction contributes to the anti-adipogenic activity of KR62980.Jung H et al
111182132000TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins.Kanai F et al
213499462011Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF.Lai D et al
236733662013BMP4 is a novel transcriptional target and mediator of mammary cell migration downstream of the Hippo pathway component TAZ.Lai D et al
244975542014Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis.Lau AN et al
182271512008TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway.Lei QY et al
220034372011Regulation and function of the TAZ transcription co-activator.Liu C et al
163329602005A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.Murakami M et al
208504372010TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner.Remue E et al
246133582014The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment.Skibinski A et al
176360282007TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex.Tian Y et al
192345252009YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease.Wang K et al
235516912013Overexpression of Hippo pathway effector TAZ in tongue squamous cell carcinoma: correlation with clinicopathological features and patients' prognosis.Wei Z et al
224812332012Prognostic significance of TAZ expression in resected non-small cell lung cancer.Xie M et al
214745622011Nek1 and TAZ interact to maintain normal levels of polycystin 2.Yim H et al
233726862013TAZ expression as a prognostic indicator in colorectal cancer.Yuen HF et al
189551392008The Hippo-YAP pathway: new connections between regulation of organ size and cancer.Zhao B et al
218082412011The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal.Zhao B et al
220450232012TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis.Zhao D et al
212584162011TAZ is a novel oncogene in non-small cell lung cancer.Zhou Z et al

Other Information

Locus ID:

NCBI: 25937
MIM: 607392
HGNC: 24042
Ensembl: ENSG00000018408


dbSNP: 25937
ClinVar: 25937
TCGA: ENSG00000018408


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Hippo signalingKEGGhsa_M00683
Hippo signalingKEGGM00683
Signal TransductionREACTOMER-HSA-162582
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimerREACTOMER-HSA-2173793
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcriptionREACTOMER-HSA-2173796
Signaling by HippoREACTOMER-HSA-2028269
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
YAP1- and WWTR1 (TAZ)-stimulated gene expressionREACTOMER-HSA-2032785
Muscle contractionREACTOMER-HSA-397014
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781
Cardiac conductionREACTOMER-HSA-5576891
Physiological factorsREACTOMER-HSA-5578768
Hippo signaling pathway -multiple speciesKEGGko04392
Hippo signaling pathway -multiple speciesKEGGhsa04392

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
216547992011Role of YAP/TAZ in mechanotransduction.1302
220788772011The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.437
239544132013A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors.411
255926482015The emerging roles of YAP and TAZ in cancer.345
273004342016YAP/TAZ at the Roots of Cancer.332
160999862005TAZ, a transcriptional modulator of mesenchymal stem cell differentiation.321
228954352012Transduction of mechanical and cytoskeletal cues by YAP and TAZ.268
185680182008TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.246
193248772009TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition.214
184137272008A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells.193


Yulei Zhao ; Xiaolong Yang

WWTR1 (WW domain containing transcription regulator 1)

Atlas Genet Cytogenet Oncol Haematol. 2014-03-01

Online version: http://atlasgeneticsoncology.org/gene/44545/wwtr1-(ww-domain-containing-transcription-regulator-1)