Alternative titles; symbols
HGNC Approved Gene Symbol: WWTR1
Cytogenetic location: 3q25.1 Genomic coordinates (GRCh38) : 3:149,517,235-149,724,788 (from NCBI)
By screening for 14-3-3 (see 605066)-binding proteins, followed by 5-prime RACE, Kanai et al. (2000) cloned TAZ (WWTR1) from a HeLa cDNA expression library. The deduced protein contains 400 amino acids and has an apparent molecular mass of 45 kD in HeLa cells. It has a putative 14-3-3 protein-binding motif in its N terminus, a central WW domain, and a putative 2-stranded coiled-coil and a PDZ-binding motif in its C terminus. WWTR1 shares 91% sequence identity with the mouse Taz protein and 45% identity with YAP (606608). Northern blot analysis revealed highest expression of a 6-kb transcript in kidney, followed by heart, placenta, and lung. Expression was detected in all tissues tested except thymus and peripheral blood leukocytes. Northern blot analysis of mouse tissues showed a 5.5-kb transcript expressed at highest levels in kidney, lung, liver, and heart; a 2.2-kb transcript was detected in testis. Western blot analysis revealed expression of Taz in several epithelial and fibroblast cell lines, but not in Jurkat T cells.
Cui et al. (2003) cloned mouse Taz. The deduced 395-amino acid protein has an N-terminal 14-3-3 protein-binding site, followed by a WW domain, a transcription activation domain, and a C-terminal PDZ-binding motif. RT-PCR analysis of 7-day-old mouse pups showed Taz expression in all tissues examined, with highest expression in calvaria and skin. Immunohistochemical analysis of transfected NIH3T3 cells revealed Taz expression throughout the cell, with highest concentration in the perinuclear area.
By radiation hybrid analysis, Kanai et al. (2000) mapped the TAZ (WWTR1) gene to chromosome 3q24.
Kanai et al. (2000) characterized murine Taz. They found that the interaction of Taz with rat 14-3-3 required Taz phosphorylation on a specific serine residue. Phosphorylation reduced Taz transcriptional coactivation by inducing nuclear export through interaction with 14-3-3. The C-terminal PDZ-binding domain localized Taz to discrete nuclear foci and was required for Taz-stimulated gene transcription. The PDZ-binding domain also mediated Taz interaction with Nherf2 (606553).
By yeast 2-hybrid analysis of a 17-day embryonic mouse cDNA library, Cui et al. (2003) found that Taz interacted with Runx2 (600211). Coexpression of Taz with Runx2 resulted in nuclear localization of both proteins and enhanced Runx2-mediated activation of an osteocalcin (BGLAP; 112260) reporter gene. Deletion of any domain in Taz reduced its cotranscriptional activity, and deletion of both the transcription activation domain and PDZ-binding domain resulted in a dominant-negative protein that inhibited Runx2-mediated reporter expression.
Mesenchymal stem cells are a pluripotent cell type that can differentiate into several distinct lineages. Two key transcription factors, RUNX2 and peroxisome proliferator-activated receptor-gamma (PPARG; 601487), drive mesenchymal stem cells to differentiate into either osteoblasts or adipocytes, respectively. Hong et al. (2005) found that TAZ, a 14-3-3-binding protein, coactivates RUNX2-dependent gene transcription while repressing PPARG-dependent gene transcription. By modulating Taz expression in model cell lines, mouse embryonic fibroblasts, and primary mesenchymal stem cells in culture and in zebrafish in vivo, Hong et al. (2005) observed alterations in osteogenic versus adipogenic potential. Hong et al. (2005) concluded that TAZ functions as a molecular rheostat that modulates mesenchymal stem cell differentiation.
Murakami et al. (2005) found that TAZ was a potent TBX5 (601620) transactivator. TAZ associated with TBX5 and stimulated TBX5-dependent promoters by interacting with the histone acetyltransferases p300 (EP300; 602700) and PCAF (602303). TBX5 with Holt-Oram syndrome (HOS; 142900)-associated truncation mutations could not be stimulated by TAZ, but TBX5 with HOS-associated point mutations was unimpaired in its ability to respond to TAZ.
Kang et al. (2009) identified mouse Wwtr1 as a critical coactivator of Glis3 (610192) transactivation activity. Coimmunoprecipitation, mammalian 2-hybrid, and protein pull-down assays showed that the 2 proteins interacted directly. The WW domain of Wwtr1 recognizes a P/LPxY motif, and Kang et al. (2009) identified 4 putative P/LPxY motifs in the Glis3 protein. Deletion and mutation analysis revealed that only the C-terminal motif (PPHY) of Glis3 was functional, and an intact PPHY motif was required for Glis3 transcriptional activation. The interaction between Glis3 and Wwtr1 resulted in redistribution of Wwtr1 from the cytosol to the nucleus of cotransfected COS-1 cells.
Dupont et al. (2011) reported the identification of YAP and TAZ as nuclear relays of mechanical signals exerted by extracellular matrix (ECM) rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behavior. Dupont et al. (2011) concluded that their findings identified YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
Using murine and human constructs, Habbig et al. (2012) found that NPHP9 (NEK8; 609799) competed with 14-3-3 for binding to TAZ protein and inhibited 14-3-3-dependent phosphorylation of TAZ on ser89. Interaction of 14-3-3 with TAZ favored retention of TAZ in the cytoplasm, whereas NPHP9 binding enhanced nuclear delivery of TAZ and augmented TAZ activity. A kinase-dead NPHP9 mutant also augmented TAZ activity. Knockdown of NPHP9 reduced TAZ-dependent cell proliferation in 2 human breast cancer cell lines. NPHP4 (607215) enhanced nuclear NPHP9 accumulation and thereby promoted the TAZ-NPHP9 interaction.
Wang et al. (2016) showed that endothelial YAP (606608)/TAZ activity is regulated by different patterns of blood flow, and YAP/TAZ inhibition suppresses inflammation and retards atherogenesis. Atheroprone-disturbed flow increased whereas atheroprotective unidirectional shear stress inhibited YAP/TAZ activity. Unidirectional shear stress activated integrin beta-3 (ITGB3; 173470) and promoted integrin/G-alpha-13 (GNA13; 604406) interaction, leading to RhoA (165390) inhibition and YAP phosphorylation and suppression. YAP/TAZ inhibition suppressed JNK (601158) signaling and downregulated proinflammatory genes expression, thereby reducing monocyte attachment and infiltration. In vivo endothelial-specific YAP overexpression exacerbated, while CRISPR/Cas9-mediated Yap knockdown in endothelium retarded, plaque formation in ApoE-null mice. Wang et al. (2016) also showed that several antiatherosclerotic agents, such as statins, inhibit YAP/TAZ transactivation. On the other hand, simvastatin failed to suppress constitutively active YAP/TAZ-induced proinflammatory gene expression in endothelial cells, indicating that YAP/TAZ inhibition could contribute to the antiinflammatory effect of simvastatin. Furthermore, activation of integrin by oral administration of manganese chloride (MnCl2) reduced plaque formation.
Using a combination of gain- and loss-of-function approaches in several cellular contexts, Chang et al. (2018) showed that YAP (606608) and TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits, and liver tumorigenesis. Chang et al. (2018) found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A (603024) and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A-SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A-SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signaling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A-SWI/SNF, thereby preventing the formation of the ARID1A-SWI/SNF-YAP/TAZ complex, in favor of an association between TEAD and YAP/TAZ. Chang et al. (2018) proposed that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signaling, and inhibition of ARID1A-SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. Chang et al. (2018) concluded that their study offered a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis.
Although the symbol TAZ is used in the literature for the gene discussed in this entry, TAZ is the official symbol for tafazzin (300394) according to the HUGO Nomenclature Committee.
By studying mouse models, Moya et al. (2019) showed that Yap and Taz exerted a tumor-suppressive function. Normal hepatocytes surrounding liver tumors exhibited activation of Yap and Taz, and deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of Yap in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Tumor cells growing in wildtype livers required Yap and Taz for survival, whereas those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on Yap and Taz. The findings revealed that tumor cell survival depends on relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.
Chang, L., Azzolin, L., Di Biagio, D., Zanconato, F., Battilana, G., Lucon Xiccato, R., Aragona, M., Giulitti, S., Panciera, T., Gandin, A., Sigismondo, G., Krijgsveld, J., Fassan, M., Brusatin, G., Cordenonsi, M., Piccolo, S. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 563: 265-269, 2018. [PubMed: 30401838] [Full Text: https://doi.org/10.1038/s41586-018-0658-1]
Cui, C. B., Cooper, L. F., Yang, X., Karsenty, G., Aukhil, I. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Molec. Cell. Biol. 23: 1004-1013, 2003. [PubMed: 12529404] [Full Text: https://doi.org/10.1128/MCB.23.3.1004-1013.2003]
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 474: 179-183, 2011. [PubMed: 21654799] [Full Text: https://doi.org/10.1038/nature10137]
Habbig, S., Bartram, M. P., Sagmuller, J. G., Griessmann, A., Franke, M., Muller, R.-U., Schwarz, R., Hoehne, M., Bergmann, C., Tessmer, C., Reinhardt, H. C., Burst, V., Benzing, T., Schermer, B. The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ. Hum. Molec. Genet. 21: 5528-5538, 2012. [PubMed: 23026745] [Full Text: https://doi.org/10.1093/hmg/dds408]
Hong, J.-H., Hwang, E. S., McManus, M. T., Amsterdam, A., Tian, Y., Kalmukova, R., Mueller, E., Benjamin, T., Spiegelman, B. M., Sharp, P. A., Hopkins, N., Yaffe, M. B. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309: 1074-1078, 2005. [PubMed: 16099986] [Full Text: https://doi.org/10.1126/science.1110955]
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. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 19: 6778-6791, 2000. [PubMed: 11118213] [Full Text: https://doi.org/10.1093/emboj/19.24.6778]
Kang, H. S., Beak, J. Y., Kim, Y.-S., Herbert, R., Jetten, A. M. Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease. Molec. Cell. Biol. 29: 2556-2569, 2009. [PubMed: 19273592] [Full Text: https://doi.org/10.1128/MCB.01620-08]
Moya, I. M., Castaldo, S. A., Van den Mooter, L., Soheily, S., Sansores-Garcia, L., Jacobs, J., Mannaerts, I., Xie, J., Verboven, E., Hillen, H., Alguero-Nadal, A., Karaman, R., and 13 others. Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice. Science 366: 1029-1034, 2019. [PubMed: 31754005] [Full Text: https://doi.org/10.1126/science.aaw9886]
Murakami, M., Nakagawa, M., Olson, E. N., Nakagawa, O. A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc. Nat. Acad. Sci. 102: 18034-18039, 2005. [PubMed: 16332960] [Full Text: https://doi.org/10.1073/pnas.0509109102]
Wang, L., Luo, J.-Y., Li, B., Tian, X. Y., Chen, L.-J., Huang, Y., Liu, J., Deng, D., Lau, C. W., Wan, S., Ai, D., Mak, K.-L. K., Tong, K. K., Kwan, K. M., Wang, N., Chiu, J.-J., Zhu, Y., Huang, Y. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540: 579-582, 2016. [PubMed: 27926730] [Full Text: https://doi.org/10.1038/nature20602]