Skip to main content
PMC home page
PMC Canada Author Manuscripts logoLink to PMC Canada Author Manuscripts
. Author manuscript; available in PMC: 2015 Sep 11.
Published in final edited form as: Atlas Genet Cytogenet Oncol Haematol. 2014 Nov 1;18(11):849–852. doi: 10.4267/2042/54169

WWTR1 (WW domain containing transcription regulator 1)

Yulei Zhao 1, Xiaolong Yang 1
PMCID: PMC4567323  CAMSID: CAMS4862  PMID: 26366208

Abstract

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.

Keywords: Oncogene, cell differentiation, transcriptional coactivator

Identity

Other names: TAZ

HGNC (Hugo): WWTR1

Location: 3q25.1

Local order TM4SF4-WWTR1-COMMD2-ANKUB1.

DNA/RNA

Description

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.

Transcription

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

TAZ structure domain.

TAZ structure domain

Open in a new tab

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.

Protein

Description

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).

Expression

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

Localisation

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).

Function

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).

Homology

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

Mutations

Note

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

Non-small cell lung cancer

Note

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).

Colorectal cancer

Note

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).

Breast cancer

Note

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).

Tongue squamous cell carcinoma (TSCC)

Note

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).

Polycystic kidney disease (PKD)

Note

TAZ knockout mice develop PKD during development. NEK1 kinase can phosphorylate TAZ, which can disable TAZ’s 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).

Holt-Oram syndrome

Note

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).

References

  1. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 2000 Dec 15;19(24):6778–91. doi: 10.1093/emboj/19.24.6778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005 Aug 12;309(5737):1074–8. doi: 10.1126/science.1110955. [DOI] [PubMed] [Google Scholar]
  3. Murakami M, Nakagawa M, Olson EN, Nakagawa O. A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18034–9. doi: 10.1073/pnas.0509109102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Tian Y, Kolb R, Hong JH, Carroll J, Li D, You J, Bronson R, Yaffe MB, Zhou J, Benjamin T. TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex. Mol Cell Biol. 2007 Sep;27(18):6383–95. doi: 10.1128/MCB.00254-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008 Apr;28(7):2426–36. doi: 10.1128/MCB.01874-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol. 2008 Dec;20(6):638–46. doi: 10.1016/j.ceb.2008.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W. TEADs mediate nuclear retention of TAZ to promote oncogenic transformation. J Biol Chem. 2009 May 22;284(21):14347–58. doi: 10.1074/jbc.M901568200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Jung H, Lee MS, Jang EJ, Ahn JH, Kang NS, Yoo SE, Bae MA, Hong JH, Hwang ES. Augmentation of PPARgamma-TAZ interaction contributes to the anti-adipogenic activity of KR62980. Biochem Pharmacol. 2009 Nov 15;78(10):1323–9. doi: 10.1016/j.bcp.2009.07.001. [DOI] [PubMed] [Google Scholar]
  9. Wang K, Degerny C, Xu M, Yang XJ. YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease. Biochem Cell Biol. 2009 Feb;87(1):77–91. doi: 10.1139/O08-114. [DOI] [PubMed] [Google Scholar]
  10. Cho HH, Shin KK, Kim YJ, Song JS, Kim JM, Bae YC, Kim CD, Jung JS. NF-kappaB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression. J Cell Physiol. 2010 Apr;223(1):168–77. doi: 10.1002/jcp.22024. [DOI] [PubMed] [Google Scholar]
  11. Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, Harris CC, McLellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang Q, Chen L, Lin L, Wendl MC, McMichael JF, Magrini VJ, Cook L, McGrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Lin L, Crowder R, Tao Y, Snider JE, Smith SM, Dukes AF, Sanderson GE, Pohl CS, Delehaunty KD, Fronick CC, Pape KA, Reed JS, Robinson JS, Hodges JS, Schierding W, Dees ND, Shen D, Locke DP, Wiechert ME, Eldred JM, Peck JB, Oberkfell BJ, Lolofie JT, Du F, Hawkins AE, O’Laughlin MD, Bernard KE, Cunningham M, Elliott G, Mason MD, Thompson DM, Jr, Ivanovich JL, Goodfellow PJ, Perou CM, Weinstock GM, Aft R, Watson M, Ley TJ, Wilson RK, Mardis ER. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature. 2010 Apr 15;464(7291):999–1005. doi: 10.1038/nature08989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M, Gettemans J. TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner. FEBS Lett. 2010 Oct 8;584(19):4175–80. doi: 10.1016/j.febslet.2010.09.020. [DOI] [PubMed] [Google Scholar]
  13. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W. Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J Biol Chem. 2011 Mar 4;286(9):7018–26. doi: 10.1074/jbc.C110.212621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011 Nov 11;147(4):759–72. doi: 10.1016/j.cell.2011.09.048. [DOI] [PubMed] [Google Scholar]
  15. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S. Role of YAP/TAZ in mechanotransduction. Nature. 2011 Jun 8;474(7350):179–83. doi: 10.1038/nature10137. [DOI] [PubMed] [Google Scholar]
  16. Lai D, Ho KC, Hao Y, Yang X. Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res. 2011 Apr 1;71(7):2728–38. doi: 10.1158/0008-5472.CAN-10-2711. [DOI] [PubMed] [Google Scholar]
  17. Liu C, Huang W, Lei Q. Regulation and function of the TAZ transcription co-activator. Int J Biochem Mol Biol. 2011;2(3):247–56. [PMC free article] [PubMed] [Google Scholar]
  18. Yim H, Sung CK, You J, Tian Y, Benjamin T. Nek1 and TAZ interact to maintain normal levels of polycystin 2. J Am Soc Nephrol. 2011 May;22(5):832–7. doi: 10.1681/ASN.2010090992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Zhao B, Tumaneng K, Guan KL. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011 Aug 1;13(8):877–83. doi: 10.1038/ncb2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Zhou Z, Hao Y, Liu N, Raptis L, Tsao MS, Yang X. TAZ is a novel oncogene in non-small cell lung cancer. Oncogene. 2011 May 5;30(18):2181–6. doi: 10.1038/onc.2010.606. [DOI] [PubMed] [Google Scholar]
  21. Hong W, Guan KL. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012 Sep;23(7):785–93. doi: 10.1016/j.semcdb.2012.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Xie M, Zhang L, He CS, Hou JH, Lin SX, Hu ZH, Xu F, Zhao HY. Prognostic significance of TAZ expression in resected non-small cell lung cancer. J Thorac Oncol. 2012 May;7(5):799–807. doi: 10.1097/JTO.0b013e318248240b. [DOI] [PubMed] [Google Scholar]
  23. Zhao D, Zhi X, Zhou Z, Chen C. TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis. Carcinogenesis. 2012 Jan;33(1):59–67. doi: 10.1093/carcin/bgr242. [DOI] [PubMed] [Google Scholar]
  24. Lai D, Yang X. BMP4 is a novel transcriptional target and mediator of mammary cell migration downstream of the Hippo pathway component TAZ. Cell Signal. 2013 Aug;25(8):1720–8. doi: 10.1016/j.cellsig.2013.05.002. [DOI] [PubMed] [Google Scholar]
  25. Wei Z, Wang Y, Li Z, Yuan C, Zhang W, Wang D, Ye J, Jiang H, Wu Y, Cheng J. Overexpression of Hippo pathway effector TAZ in tongue squamous cell carcinoma: correlation with clinicopathological features and patients’ prognosis. J Oral Pathol Med. 2013 Nov;42(10):747–54. doi: 10.1111/jop.12062. [DOI] [PubMed] [Google Scholar]
  26. Yuen HF, McCrudden CM, Huang YH, Tham JM, Zhang X, Zeng Q, Zhang SD, Hong W. TAZ expression as a prognostic indicator in colorectal cancer. PLoS One. 2013;8(1):e54211. doi: 10.1371/journal.pone.0054211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Bartucci M, Dattilo R, Moriconi C, Pagliuca A, Mottolese M, Federici G, Benedetto AD, Todaro M, Stassi G, Sperati F, Amabile MI, Pilozzi E, Patrizii M, Biffoni M, Maugeri-Saccà M, Piccolo S, De Maria R. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene. 2014 Feb 17; doi: 10.1038/onc.2014.5. [DOI] [PubMed] [Google Scholar]
  28. Lau AN, Curtis SJ, Fillmore CM, Rowbotham SP, Mohseni M, Wagner DE, Beede AM, Montoro DT, Sinkevicius KW, Walton ZE, Barrios J, Weiss DJ, Camargo FD, Wong KK, Kim CF. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis. EMBO J. 2014 Mar 3;33(5):468–81. doi: 10.1002/embj.201386082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Skibinski A, Breindel JL, Prat A, Galván P, Smith E, Rolfs A, Gupta PB, Labaer J, Kuperwasser C. The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment. Cell Rep. 2014 Mar 27;6(6):1059–72. doi: 10.1016/j.celrep.2014.02.038. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES