WWTR1

File:Prredicted WWTR1 Structure - AlphaFold.png.{{Cite web |title=AlphaFold Protein Structure Database |url=https://alphafold.ebi.ac.uk/entry/Q9GZV5 |access-date=2022-11-23 |website=alphafold.ebi.ac.uk}}]]

File:YAP vs TAZ Binding Domains.png

WWTR1 contains a proline rich region, TEAD binding motif, WW domain, coiled coil region, and a transactivation domain (TAD) containing the PDZ domain-binding motif. WWTR1 (TAZ) lacks a DNA binding domain so it can not directly drive transcription. WWTR1 exhibits conserved structural homology with another transcriptional coregulator, yes-associated protein 1 (YAP). Both YAP and TAZ are able to form homodimers and heterodimers with each other through interactions at the coil coil domain.{{cite journal |vauthors=Callus BA, Finch-Edmondson ML, Fletcher S, Wilton SD |date=February 2019 |title=YAPping about and not forgetting TAZ |journal=FEBS Letters |volume=593 |issue=3 |pages=253–276 |doi=10.1002/1873-3468.13318 |pmid=30570758 |s2cid=58578804|doi-access=free }} YAP and TAZ cooperate with transcription factors to promote tissue formation. WWTR1 (TAZ) interacts with a variety of transcriptional partners, including the four TEA domain family members (TEAD1/2/3/4) through the TEAD-binding motif and several other factors containing the PPXY motif, which consists of a Proline-Proline-X (any amino acid)-Tyrosine sequence. Examples of such partners include Runx/PEBP2, AP2, C/EBP, c-Jun, Krox-20, Krox-24, MEF2B, NF-E2, Oct-4 and p73, which interact with WWTR1 via the WW domain. The transactivation domain at the C-terminal end (amino acids 165–395) was shown to be important in producing transcriptional effects.

File:YAP and TAZ - Biochemical Regulation Diagram.png

WWTR1 (TAZ) plays an important role in embryogenesis and development,{{cite journal | vauthors = Wu Z, Guan KL | title = Hippo Signaling in Embryogenesis and Development | journal = Trends in Biochemical Sciences | volume = 46 | issue = 1 | pages = 51–63 | date = January 2021 | pmid = 32928629 | pmc = 7749079 | doi = 10.1016/j.tibs.2020.08.008 }}{{cite journal | vauthors = Zheng Y, Pan D | title = The Hippo Signaling Pathway in Development and Disease | journal = Developmental Cell | volume = 50 | issue = 3 | pages = 264–282 | date = August 2019 | pmid = 31386861 | pmc = 6748048 | doi = 10.1016/j.devcel.2019.06.003 }} which include regulation of organ size,{{cite journal | vauthors = Piccolo S, Dupont S, Cordenonsi M | title = The biology of YAP/TAZ: hippo signaling and beyond | journal = Physiological Reviews | volume = 94 | issue = 4 | pages = 1287–1312 | date = October 2014 | pmid = 25287865 | doi = 10.1152/physrev.00005.2014 }}{{cite journal | vauthors = Pocaterra A, Romani P, Dupont S | title = YAP/TAZ functions and their regulation at a glance | journal = Journal of Cell Science | volume = 133 | issue = 2 | pages = jcs230425 | date = January 2020 | pmid = 31996398 | doi = 10.1242/jcs.230425 | hdl = 11577/3317485 | s2cid = 210945848 | hdl-access = free }}{{cite journal | vauthors = Totaro A, Panciera T, Piccolo S | title = YAP/TAZ upstream signals and downstream responses | journal = Nature Cell Biology | volume = 20 | issue = 8 | pages = 888–899 | date = August 2018 | pmid = 30050119 | pmc = 6186418 | doi = 10.1038/s41556-018-0142-z }} stem cell renewal, tissue regeneration,{{cite journal | vauthors = Driskill JH, Pan D | title = The Hippo Pathway in Liver Homeostasis and Pathophysiology | journal = Annual Review of Pathology | volume = 16 | pages = 299–322 | date = January 2021 | pmid = 33234023 | pmc = 8594752 | doi = 10.1146/annurev-pathol-030420-105050 }}{{cite journal | vauthors = Moya IM, Halder G | title = Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine | journal = Nature Reviews. Molecular Cell Biology | volume = 20 | issue = 4 | pages = 211–226 | date = April 2019 | pmid = 30546055 | doi = 10.1038/s41580-018-0086-y | s2cid = 54820180 | url = https://lirias.kuleuven.be/handle/123456789/633380 | url-access = subscription }} osteogenesis,{{cite journal | vauthors = Kovar H, Bierbaumer L, Radic-Sarikas B | title = The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis | journal = Cells | volume = 9 | issue = 4 | pages = 972 | date = April 2020 | pmid = 32326412 | pmc = 7227004 | doi = 10.3390/cells9040972 | doi-access = free }} and angiogenesis.{{cite journal | vauthors = Boopathy GT, Hong W | title = Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis | journal = Frontiers in Cell and Developmental Biology | volume = 7 | pages = 49 | date = 2019 | pmid = 31024911 | pmc = 6468149 | doi = 10.3389/fcell.2019.00049 | doi-access = free }} These functions are effected through coactivation of transcription factors that promote cell growth, migration, and differentiation, such as the four members of the TEAD transcription factor family, Paired box gene 3 (PAX3), and Runt related transcription factors (RUNX1/)2). The proliferative functions of WWTR1 (TAZ) and its paralog, YAP, are restricted by the Hippo signaling pathway.{{cite journal | vauthors = Heng BC, Zhang X, Aubel D, Bai Y, Li X, Wei Y, Fussenegger M, Deng X | title = An overview of signaling pathways regulating YAP/TAZ activity | journal = Cellular and Molecular Life Sciences | volume = 78 | issue = 2 | pages = 497–512 | date = January 2021 | pmid = 32748155 | doi = 10.1007/s00018-020-03579-8 | s2cid = 220930261 | pmc = 11071991 }}{{cite journal | vauthors = Ma S, Meng Z, Chen R, Guan KL | title = The Hippo Pathway: Biology and Pathophysiology | journal = Annual Review of Biochemistry | volume = 88 | pages = 577–604 | date = June 2019 | pmid = 30566373 | doi = 10.1146/annurev-biochem-013118-111829 | s2cid = 58642425 }}{{cite journal | vauthors = Meng Z, Moroishi T, Guan KL | title = Mechanisms of Hippo pathway regulation | journal = Genes & Development | volume = 30 | issue = 1 | pages = 1–17 | date = January 2016 | pmid = 26728553 | pmc = 4701972 | doi = 10.1101/gad.274027.115 }} This suppressive pathway consists of a kinase signaling cascade, the core of which is made up of the serine-threonine kinases, STK3/MST2 and STK4/MST1, which when active and complexed with the regulatory protein, SAV1, will phosphorylate and activate the LATS1/2 kinases, which in complex with the regulatory protein, MOB1, phosphorylate and downstream inactivate YAP/TAZ.{{Cite web |title=UniProt - Q9GZV5 · WWTR1_HUMAN |url=https://www.uniprot.org/uniprotkb/Q9GZV5/entry |access-date=2022-11-17 |website=www.uniprot.org}} In this way, Hippo activation arrests cell growth by decreasing proliferative gene expression, leading to decreased cell death by ferroptosis{{cite journal | vauthors = Sun T, Chi JT | title = Regulation of ferroptosis in cancer cells by YAP/TAZ and Hippo pathways: The therapeutic implications | journal = Genes & Diseases | volume = 8 | issue = 3 | pages = 241–249 | date = May 2021 | pmid = 33997171 | pmc = 8093643 | doi = 10.1016/j.gendis.2020.05.004 }}{{cite journal | vauthors = Dai C, Chen X, Li J, Comish P, Kang R, Tang D | title = Transcription factors in ferroptotic cell death | journal = Cancer Gene Therapy | volume = 27 | issue = 9 | pages = 645–656 | date = September 2020 | pmid = 32123318 | doi = 10.1038/s41417-020-0170-2 | s2cid = 211728890 | doi-access = free }} and increased cell death by apoptosis.

WWTR1 (TAZ) has a similar structural sequence and binding motifs to yes-associated protein 1 (YAP). YAP and TAZ are often considered functionally redundant in existing literature.{{cite journal | vauthors = Reggiani F, Gobbi G, Ciarrocchi A, Sancisi V | title = YAP and TAZ Are Not Identical Twins | language = English | journal = Trends in Biochemical Sciences | volume = 46 | issue = 2 | pages = 154–168 | date = February 2021 | pmid = 32981815 | doi = 10.1016/j.tibs.2020.08.012 | s2cid = 222166778 }} Both play roles in organ size development as well as cell migration, wound healing, angiogenesis, and metabolism, particularly in lipogenesis.{{cite journal | vauthors = Koo JH, Guan KL | title = Interplay between YAP/TAZ and Metabolism | language = English | journal = Cell Metabolism | volume = 28 | issue = 2 | pages = 196–206 | date = August 2018 | pmid = 30089241 | doi = 10.1016/j.cmet.2018.07.010 | s2cid = 51939438 | doi-access = free }} Inactivation of YAP and TAZ occurs through phosphorylation by kinases in the Hippo pathway, namely LATS1 and LATS2. This recruits the binding of the regulatory protein, 14-3-3, which prevents YAP/TAZ from localizing to the nucleus and marks it for ubiquitination, which allows it to be recognized for subsequent degradation by proteasomes.

TAZ is able to form both heterodimers and heterotetramers with TEADs to initiate transcription (TAZ-TEAD and TAZ-TEAD-TAZ-TEAD), while YAP is only able to form YAP-TEAD heterodimers. These differences impart unique functions to TAZ, such as in the regulation of adipocyte differentiation through interactions with the peroxisome proliferator-activated receptor (PPARγ), as well as osteogenesis through transcriptional coactivation of bone-specific transcription factors, such as RUNX2 (also known as Cbfa1.) Additionally, TAZ independently interacts with Nuclear factor of activated T-cells 5 (NFATC5) in order to repress transcription in renal cells that are undergoing osmotic stress. Both YAP and TAZ associate with Mothers against decapentaplegic family transcription factors (SMAD) complexes to promote TGF-beta signaling and drive differentiation and development, but upregulation of only TAZ occurs upon transduction of this cascade. TAZ is only able to complex with SMAD2, SMAD3, or SMAD4 to promote nuclear shuttling and transcription, but YAP can also interact with SMAD1 and SMAD7 in addition. In vivo murine studies have demonstrated that animals lacking functional TAZ are more viable than animals lacking YAP expression. In contrast, silencing of YAP contributed to a more dramatic effect on cell expansion, glucose uptake, and cell cycle arrest than TAZ. When assayed in non-small-cell lung cancer (NSCLC) cell lines, WWTR1 maintained the extracellular matrix (ECM) organization and adhesion, and controlled migration more than YAP, which more closely regulated cell division and cell cycle progression genes.

File:Structure of TAZ-TEAD complex (Mouse) - Protein Data Bank.pngFile:14-3-3 sigma in complex with TAZ pS89 peptide - Protein Data Bank.png

WWTR1 has been implicated in many inflammatory diseases, including cancers.

WWTR1 (TAZ) is implicated a wide variety of cancers including melanoma, head and neck squamous cell carcinoma, breast cancer, non-small cell lung cancer, and others due to its high gene and histological expression, as well as correlation with increased metastasis and poorer survival in animal studies and patient data. Along with the structurally similar co-regulator YAP, many studies have described their role in promoting oncogenesis, altering neoplastic metabolism, and generating resistance to therapeutic intervention.{{cite journal | vauthors = Zhang X, Zhao H, Li Y, Xia D, Yang L, Ma Y, Li H | title = The role of YAP/TAZ activity in cancer metabolic reprogramming | journal = Molecular Cancer | volume = 17 | issue = 1 | pages = 134 | date = September 2018 | pmid = 30176928 | doi = 10.1186/s12943-018-0882-1 | pmc = 6122186 | doi-access = free }}{{cite journal | vauthors = Zanconato F, Cordenonsi M, Piccolo S | title = YAP/TAZ at the Roots of Cancer | language = English | journal = Cancer Cell | volume = 29 | issue = 6 | pages = 783–803 | date = June 2016 | pmid = 27300434 | pmc = 6186419 | doi = 10.1016/j.ccell.2016.05.005 }}{{cite journal | vauthors = Thompson BJ | title = YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy | journal = BioEssays | volume = 42 | issue = 5 | pages = e1900162 | date = May 2020 | pmid = 32128850 | doi = 10.1002/bies.201900162 | s2cid = 212405819 | hdl = 1885/211659 | hdl-access = free }}{{cite journal | vauthors = Zanconato F, Cordenonsi M, Piccolo S | title = YAP and TAZ: a signalling hub of the tumour microenvironment | journal = Nature Reviews. Cancer | volume = 19 | issue = 8 | pages = 454–464 | date = August 2019 | pmid = 31270418 | doi = 10.1038/s41568-019-0168-y | s2cid = 195791034 }} In particular, TAZ overexpression conferred resistance to cisplatin chemotherapy as well as immunotherapy treatment with a PD-1 antibody.

File:Protein Atlas WWTR1 Protein Expression Medium Intensity - CAB017483 - Patient 5427 and 4940.png

YAP and TAZ function have been targeted in several therapeutic methods in the treatment of cancers.

The Hippo signaling agonist, C19, increases the phosphorylation of MST1/2 and LATS1/2, resulting in more downstream inactivation of YAP/TAZ. Modulating extracellular matrix stiffness and tension using thiazovivin, cucurbitacin I, dasatinib, fluvastatin, and pazopanib, exhibited positive results in breast cancer cell lines by preventing YAP/WWTR1 translocation to the nucleus.{{cite journal | vauthors = Andl T, Zhou L, Yang K, Kadekaro AL, Zhang Y | title = YAP and WWTR1: New targets for skin cancer treatment | journal = Cancer Letters | volume = 396 | pages = 30–41 | date = June 2017 | pmid = 28279717 | doi = 10.1016/j.canlet.2017.03.001 }} Endogenous hormonal factors that are synthesized for normal physiological functions such as epinephrine and glucagon have also been demonstrated to have similar inhibitory effects on YAP/TAZ function by promoting Hippo pathway activation. The class of cholesterol inhibitors, statins, was shown to inhibit the Rho family of GTP-ases (Rho-GTPase), which are enzymes that signal for upstream inhibition of the Hippo pathway, and exhibited similar effects in attenuating growth of breast cancer and human lung adenocarcinoma cells. Statins inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), which is the precursor to mevalonate in the mevalonate pathway that synthesizes the lipid building blocks that form cholesterols and the lipid chains responsible for anchoring Rho-GTPases to the cell membrane. The Rho-GTPase, Ras Family Homolog A (RhoA), is activated by prenlylation (the posttranslational modification through addition of hydrophobic groups), and is responsible in part for modulating cytoskeletal elements that reduce Hippo pathway activity. By targeting Rho kinases with thiazovivin, or lipid synthesis through the mevalonate pathway, with statins, RhoA is inhibited and increased Hippo kinase activity may limit proliferation driven by YAP/TAZ. Tyrosine kinases signal in proliferative pathways, some which promote YAP/TAZ function, such as Src family kinases and includes the Yes tyrosine kinase, which is associated with YAP function. Targeting tyrosine kinases with inhibitors such as dasatinib and pazopanib has shown some effect in cancers.

Inhibition of YAP/TAZ function by targeting their interactions with their transcriptional partners in the TEAD family has also been studied.{{cite journal | vauthors = Pobbati AV, Hong W | title = A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy | journal = Theranostics | volume = 10 | issue = 8 | pages = 3622–3635 | date = 2020 | pmid = 32206112 | pmc = 7069086 | doi = 10.7150/thno.40889 }} This includes the use of verteporfin, which was investigated in the treatment of skin cancers, particularly melanoma, although it was not taken beyond preclinical studies.

{{Reflist}}

Category:Wikipedia Student Program