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WW domain-containing transcription regulator protein 1 (WWTR1), also known as
Transcriptional coactivator A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA p ...
with PDZ-binding motif (TAZ), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
that in humans is encoded by the ''WWTR1''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. WWTR1 acts as a transcriptional coregulator and has no effect on transcription alone. When in complex with
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
binding partners, WWTR1 helps promote
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...
in pathways associated with development, cell growth and survival, and inhibiting apoptosis. Aberrant WWTR1 function has been implicated for its role in driving
cancers Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...
. WWTR1 is often referred to as TAZ due to its initial characterization with the name TAZ. However, WWTR1 (TAZ) is not to be confused with the protein tafazzin, which originally held the official gene symbol TAZ, and is now TAFAZZIN.


Structure

WWTR1 contains a proline rich region, TEAD binding motif,
WW domain The WW domain, (also known as the rsp5-domain or WWP repeating motif) is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be ...
, coiled coil region, and a transactivation domain (TAD) containing the
PDZ domain The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane t ...
-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. 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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
)-
Tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
sequence. Examples of such partners include Runx/PEBP2, AP2, C/EBP,
c-Jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only la ...
, 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
end (amino acids 165–395) was shown to be important in producing transcriptional effects.


Function

WWTR1 (TAZ) plays an important role in
embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
and development, which include regulation of organ size,
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
renewal, tissue regeneration, osteogenesis, and angiogenesis. 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. This suppressive pathway consists of a kinase signaling cascade, the core of which is made up of the serine-threonine kinases,
STK3 Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the ''STK3'' gene. Background Protein kinase activation is a frequent response of cells to treatment with growth factors, chemicals, heat shock, or apoptosis-inducing ag ...
/
MST2 Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the ''STK3'' gene. Background Protein kinase activation is a frequent response of cells to treatment with growth factors, chemicals, heat shock, or apoptosis-inducing ...
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. In this way, Hippo activation arrests cell growth by decreasing proliferative gene expression, leading to decreased cell death by ferroptosis and increased
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
by apoptosis.


Functional Redundancy with Yes Associated Protein (YAP)


Similarities

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. Both play roles in organ size development as well as
cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...
,
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier aga ...
, angiogenesis, and
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
, particularly in
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synt ...
. Inactivation of YAP and TAZ occurs through
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
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 Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...
and marks it for
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. F ...
, which allows it to be recognized for subsequent degradation by proteasomes.


Differences

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 Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesi ...
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 Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentiat ...
.) 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 Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins. It acts as a mediator of the signals initiated by t ...
, 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 Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, usi ...
uptake, and
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and sub ...
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.


WWTR1 Protein Interactions


Clinical Significance


Roles in Diseases

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


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. In particular, TAZ overexpression conferred resistance to
cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelio ...
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
as well as
immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
treatment with a PD-1 antibody.


Associated Therapeutics

YAP and TAZ function have been targeted in several therapeutic methods in the treatment of cancers. The Hippo signaling
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
, C19, increases the phosphorylation of MST1/2 and LATS1/2, resulting in more downstream inactivation of YAP/TAZ. Modulating
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
stiffness and tension using
thiazovivin Thiazovivin is a drug which acts as a potent and selective inhibitor of the enzyme Rho kinase. It is used alongside a cocktail of other growth factors and modulators in cell culture techniques for the generation of induced pluripotent stem cells ...
,
cucurbitacin I Cucurbitacin is a class of biochemical compounds that some plants – notably members of the pumpkin and gourd family, Cucurbitaceae – produce and which function as a defence against herbivores. Cucurbitacins are chemically classified as t ...
, dasatinib,
fluvastatin Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease. It was patented in 1982 and approved for medical use in 1994. It is on the World Health Organization's List of Essential ...
, and pazopanib, exhibited positive results in breast cancer cell lines by preventing YAP/WWTR1 translocation to the nucleus. 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 Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
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 Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to d ...
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 Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids incl ...
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. This includes the use of
verteporfin Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degen ...
, which was investigated in the treatment of skin cancers, particularly melanoma, although it was not taken beyond preclinical studies.


References

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