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WWTR1
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<h2 id="structure">Structure</h2> <p>WWTR1 contains a <a href="/facts/Proline/x1ABSW5A">proline</a> rich region, <a href="/facts/TEAD2/k6XIee6t">TEAD</a> binding motif, <a href="/facts/WW_domain/se8s4D5V">WW domain</a>, <a href="/facts/Coiled_coil/U0YEzcB4">coiled coil</a> region, and a <a href="/facts/Transactivation_domain/vdmz1ulg">transactivation domain (TAD)</a> containing the <a href="/facts/PDZ_domain/kSanExq4">PDZ domain</a>-binding motif. WWTR1 (TAZ) lacks a <a href="/facts/DNA-binding_domain/x2vlHUKl">DNA binding domain</a> so it can not directly drive transcription. WWTR1 exhibits conserved <a href="/facts/Structural_homology/FJTXCha0">structural homology</a> with another transcriptional coregulator, <a href="/facts/YAP1/jl4okjo9">yes-associated protein 1 (YAP)</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> Both YAP and TAZ are able to form <a href="/facts/Homodimers/c8LwFJPG">homodimers</a> and <a href="/facts/Heterodimers/c8LwFJPG">heterodimers</a> with each other through interactions at the coil coil domain.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> YAP and TAZ cooperate with transcription factors to promote <a href="/facts/Tissue_(biology)/H7CpML7A">tissue</a> formation. WWTR1 (TAZ) interacts with a variety of transcriptional partners, including the four TEA domain family members (<a href="/facts/TEAD1/X6KLXfkc">TEAD1</a><a href="/facts/TEAD2/k6XIee6t">/2/</a><a href="/facts/TEAD3/BzXe0Fxp">3/</a><a href="/facts/TEAD4/tURax9hM">4</a>) through the TEAD-binding motif and several other factors containing the PPXY motif, which consists of a <a href="/facts/Proline/x1ABSW5A">Proline</a>-<a href="/facts/Proline/x1ABSW5A">Proline</a>-X (any <a href="/facts/Amino_acid/WDxYwBny">amino acid</a>)-<a href="/facts/Tyrosine/RJhEgE4C">Tyrosine</a> sequence. Examples of such partners include Runx/PEBP2, <a href="/facts/AP2_adaptor_complex/38D5ytjK">AP2</a>, C/EBP, <a href="/facts/Transcription_factor_Jun/Cbvb15yT">c-Jun</a>, <a href="/facts/EGR2/0r3S37Ky">Krox-20</a>, <a href="/facts/EGR1/nbqUEnvG">Krox-24</a>, <a href="/facts/MEF2B/PaDwK3Lm">MEF2B</a>, <a href="/facts/NFE2/7q0DE54B">NF-E2</a>, <a href="/facts/Oct-4/Vee10vjH">Oct-4</a> and <a href="/facts/P73/DM92hxht">p73</a>, which interact with WWTR1 via the WW domain.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> The transactivation domain at the <a href="/facts/C-terminus/ws4scHgT">C-terminal</a> end (amino acids 165–395) was shown to be important in producing transcriptional effects.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="function">Function</h2> <p>WWTR1 (TAZ) plays an important role in <a href="/facts/Embryo/9QHnLVLN">embryogenesis</a> and <a href="/facts/Cell_development/kdIBGHub">development</a>,<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> which include regulation of organ size,<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> <a href="/facts/Stem_cell/qgB9dFrI">stem cell</a> renewal,<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> <a href="/facts/Tissue_regeneration/DHkSrakp">tissue regeneration</a>,<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> <a href="/facts/Osteogenesis/N6mMDQvR">osteogenesis</a>,<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> and <a href="/facts/Angiogenesis/h0HF9IUd">angiogenesis</a>.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> These functions are effected through coactivation of transcription factors that promote cell growth, migration, and differentiation,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> such as the four members of the TEAD transcription factor family, <a href="/facts/PAX3/zNsNrLtl">Paired box gene 3 (PAX3)</a>, and <a href="/facts/RUNX1/GAgvmcQl">Runt related transcription factors (RUNX1/)</a><a href="/facts/RUNX2/df5KyHup">2</a>).<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> The proliferative functions of WWTR1 (TAZ) and its paralog, YAP, are restricted by the <a href="/facts/Hippo_signaling_pathway/4Xs0NBPk">Hippo signaling pathway</a>.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> This suppressive pathway consists of a kinase signaling cascade, the core of which is made up of the <a href="/facts/Serine%2fthreonine-specific_protein_kinase/QKSTb82e">serine-threonine kinases</a>, <a href="/facts/STK3/lSjtvEAf">STK3</a>/<a href="/facts/MST2/lSjtvEAf">MST2</a> and <a href="/facts/STK4/jn69slPF">STK4</a>/<a href="/facts/MST1/cv7IySj7">MST1</a>, which when active and complexed with the <a href="/facts/Regulatory_protein/9N4G341I">regulatory protein</a>, <a href="/facts/SAV1/9H0mm7Pc">SAV1</a>, will phosphorylate and activate the <a href="/facts/LATS1/Sl4Cl9FB">LATS1</a><a href="/facts/LATS2/fxTrg1Yj">/2</a> kinases, which in complex with the regulatory protein, <a href="/facts/MOB1A/7DKTS3Ye">MOB1</a>, phosphorylate and downstream inactivate YAP/TAZ.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> In this way, Hippo activation arrests cell growth by decreasing proliferative gene expression, leading to decreased cell death by <a href="/facts/Ferroptosis/wL53toRk">ferroptosis</a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> and increased <a href="/facts/Cell_death/UYCzvewT">cell death</a> by <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> </p> <h3>Functional redundancy with YAP</h3> <h4>Similarities</h4> <p>WWTR1 (TAZ) has a similar structural sequence and binding motifs to <a href="/facts/YAP1/jl4okjo9">yes-associated protein 1 (YAP)</a>.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> YAP and TAZ are often considered functionally redundant in existing literature.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> Both play roles in organ size development as well as <a href="/facts/Cell_migration/5ySAMquQ">cell migration</a>, <a href="/facts/Wound_healing/3NlzV5Qn">wound healing</a>, <a href="/facts/Angiogenesis/h0HF9IUd">angiogenesis</a>, and <a href="/facts/Metabolism/WxDrm8k5">metabolism</a>, particularly in <a href="/facts/Lipogenesis/ur2r9sbV">lipogenesis</a>.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> Inactivation of YAP and TAZ occurs through <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> by kinases in the Hippo pathway, namely LATS1 and LATS2.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> This recruits the binding of the regulatory protein, <a href="/facts/14-3-3_protein/260dE39l">14-3-3</a>, which prevents YAP/TAZ from localizing to the <a href="/facts/Cell_nucleus/D7sFRa3c">nucleus</a> and marks it for <a href="/facts/Ubiquitination/hpulmU3m">ubiquitination</a>, which allows it to be recognized for subsequent degradation by <a href="/facts/Proteasome/8vTtg2MI">proteasomes</a>.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p> <h4>Differences</h4> <p>TAZ is able to form both <a href="/facts/Heterodimers/c8LwFJPG">heterodimers</a> and <a href="/facts/Heterotetramer/bpk1VucR">heterotetramers</a> with TEADs to initiate transcription (TAZ-TEAD and TAZ-TEAD-TAZ-TEAD), while YAP is only able to form YAP-TEAD <a href="/facts/Heterodimers/c8LwFJPG">heterodimers</a>.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> These differences impart unique functions to TAZ, such as in the regulation of <a href="/facts/Adipocyte/FuM7LlaK">adipocyte</a> differentiation through interactions with the <a href="/facts/Peroxisome_proliferator-activated_receptor_gamma/V1vfQ5pP">peroxisome proliferator-activated receptor (PPARγ)</a>, as well as <a href="/facts/Osteogenesis/N6mMDQvR">osteogenesis</a> through transcriptional coactivation of bone-specific transcription factors, such as <a href="/facts/RUNX2/df5KyHup">RUNX2</a> (also known as <a href="/facts/CBFA1/df5KyHup">Cbfa1</a>.)<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> Additionally, TAZ independently interacts with <a href="/facts/NFAT5/B19oxFYN">Nuclear factor of activated T-cells 5 (NFATC5)</a> in order to repress transcription in renal cells that are undergoing <a href="/facts/Osmotic_stress/VX1lhRsE">osmotic stress</a>.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> Both YAP and TAZ associate with <a href="/facts/SMAD_(protein)/aIWIB7Nq">Mothers against decapentaplegic family transcription factors (SMAD)</a> complexes to promote <a href="/facts/TGF_beta_signaling_pathway/noWb0BFJ">TGF-beta signaling</a> and drive differentiation and development, but upregulation of only TAZ occurs upon transduction of this cascade.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> TAZ is only able to complex with <a href="/facts/Mothers_against_decapentaplegic_homolog_2/xlS5oygm">SMAD2</a>, <a href="/facts/Mothers_against_decapentaplegic_homolog_3/6j6Go6va">SMAD3</a>, or <a href="/facts/SMAD4/cgvz1vKP">SMAD4</a> to promote nuclear shuttling and transcription, but YAP can also interact with <a href="/facts/Mothers_against_decapentaplegic_homolog_1/cYgoEr7r">SMAD1</a> and <a href="/facts/Mothers_against_decapentaplegic_homolog_7/p25Strg0">SMAD7</a> in addition.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> In vivo murine studies have demonstrated that animals lacking functional TAZ are more viable than animals lacking YAP expression.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> In contrast, silencing of YAP contributed to a more dramatic effect on cell expansion, <a href="/facts/Glucose/oUSkoLCD">glucose</a> uptake, and <a href="/facts/Cell_cycle/nLMT7K4r">cell cycle</a> arrest than TAZ.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> When assayed in <a href="/facts/Non-Small_Cell_Lung_Cancer/9T47knRp">non-small-cell lung cancer (NSCLC)</a> cell lines, WWTR1 maintained the <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular matrix (ECM)</a> organization and adhesion, and controlled migration more than YAP, which more closely regulated cell division and cell cycle progression genes.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> </p> <h2 id="protein-interactions">Protein interactions</h2> <table><tbody><tr><th>Protein Interaction Partner</th><th>Functional Effects</th></tr><tr><td><a href="/facts/AMOT/ntHLPNKM">AMOT</a>, Angiomotin</td><td>Binding sequesters YAP/TAZ in the cytoplasm, inhibiting their function<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a></td></tr><tr><td><a href="/facts/Activator_protein_1/jryICv0m">AP-1, Activator protein 1</a></td><td>Promoting trancsription<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a></td></tr><tr><td><a href="/facts/ASPP2/Eha0wLXm">ASPP2</a>, Apoptosis-stimulating protein of p53</td><td>Promotes dephosphorylation and stabilization of WWTR1 (TAZ)<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a></td></tr><tr><td><a href="/facts/%25CE%2592-catenin/5eQzonk1">β-catenin</a></td><td>Recruits a destruction complex that inactivates YAP/TAZ<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a></td></tr><tr><td><a href="/facts/LATS1/Sl4Cl9FB">LATS1</a>/<a href="/facts/LATS2/fxTrg1Yj">LATS2</a>, Large tumor suppressor kinases</td><td>Phosphorylation of WWTR1, marking it for ubiquination<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a></td></tr><tr><td><a href="/facts/NFAT5/B19oxFYN">NFATC5</a>, Nuclear factor of activated T-cells 5</td><td>Represses transcription in renal cells undergoing osmotic stress<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a></td></tr><tr><td>PF, Parafibromin</td><td>Stimulates WWTR1 (TAZ) function<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a></td></tr><tr><td><a href="/facts/PAX3/zNsNrLtl">PAX3</a>, Paired box gene 3</td><td>Promoting transcription<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a></td></tr><tr><td><a href="/facts/PAX8/5kqrAwbm">PAX8</a> (<a href="/facts/PAX8/5kqrAwbm">Paired box gene 8</a>) and <a href="/facts/NKX2-2/7Mtdm1m9">NKX2-4</a> (NK homeobox)<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a></td><td>Coactivation of transcription factors involved in thyroid regulation<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a></td></tr><tr><td>PRRG4, Proline Rich And Gla Domain 4<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a></td><td>Suppressing transcription<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a></td></tr><tr><td><a href="/facts/RUNX1/GAgvmcQl">RUNX1</a><a href="/facts/RUNX2/df5KyHup">/2</a>, Runt related transcription factors</td><td>Promotes transcription<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a></td></tr><tr><td><a href="/facts/SMAD2/xlS5oygm">SMAD2</a><a href="/facts/Smad3/6j6Go6va">/3</a><a href="/facts/Mothers_against_decapentaplegic_homolog_4/cgvz1vKP">/4</a>, Mothers against decapentaplegic family transcription factors</td><td>Nuclear shuttling; promoting transcription<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a></td></tr><tr><td><a href="/facts/STAT_protein/E4L08eEa">STAT1</a>, Signal transducer and activator of transcription</td><td>Inhibiting STAT1/2 dimerization in metabolism<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a></td></tr><tr><td><a href="/facts/TEAD1/X6KLXfkc">TEAD1</a>, TEA domain family member<a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a></td><td rowspan="4">Transcriptional activation<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a></td></tr><tr><td><a href="/facts/TEAD2/k6XIee6t">TEAD2</a>, TEA domain family member,<a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a></td></tr><tr><td><a href="/facts/TEAD3/BzXe0Fxp">TEAD3</a>, TEA domain family member,<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a></td></tr><tr><td><a href="/facts/TEAD4/tURax9hM">TEAD4</a>, TEA domain family member<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a></td></tr><tr><td><a href="/facts/YAP1/jl4okjo9">YAP1</a>, Yes-associated protein 1</td><td>Dimerization dependent transcriptional regulation<a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a></td></tr><tr><td><a href="/facts/14-3-3_protein/260dE39l">YWHAE (14-3-3)</a>, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Epsilon<a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a></td><td>Restricts WWTR1 translocation to the nucleus<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a></td></tr><tr><td><a href="/facts/Tight_junction_protein_2/U6TFTRSE">ZO-2</a>, Tight junction protein 2</td><td>Localizes YAP/TAZ to the nucleus for increased activity<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a></td></tr></tbody></table> <h2 id="clinical-significance">Clinical significance</h2> <h3>Roles in disease</h3> <p>WWTR1 has been implicated in many inflammatory diseases, including cancers. </p> <table><tbody><tr><th>Disease</th><th>Clinical Significance of WWTR1</th></tr><tr><td><a href="/facts/Cancer/PVW6n1D0">Cancer</a></td><td>Associated with <a href="/facts/Metastasis/4dadbm6z">metastasis</a> and poor survival prognosis across many cancer types<a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a></td></tr><tr><td><a href="/facts/Steatohepatitis/AB657ut0">Steatohepatitis</a></td><td>Overexpression of WWTR1 progresses simple <a href="/facts/Steatosis/kS1DX4Py">steatosis</a> to <a href="/facts/Steatohepatitis/AB657ut0">steatohepatitis</a> by promoting fibrosis<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a></td></tr><tr><td><a href="/facts/Atherosclerosis/WIS8QQ6v">Atherosclerosis</a></td><td>Drives excessive endothelial cell proliferation and inflammation<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a></td></tr><tr><td><a href="/facts/Sj%25C3%25B6gren_syndrome/U1p9IbFU">Sjogren Syndrome</a></td><td>Decreased WWTR1 localization to the nucleus results in lack of functional salivary/lacrimal gland development<a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a></td></tr><tr><td><a href="/facts/Hypertension/wlAvBfcf">Hypertension</a></td><td>Activation of YAP/TAZ promotes glutamine metabolism and increases pulmonary blood pressure<a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a></td></tr><tr><td><a href="/facts/Psoriasis/WW1k1LsH">Psoriasis</a></td><td rowspan="4">YAP/TAZ activation drive pathologic angiogenesis and inflammation associated with chronic skin disorders<a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a></td></tr><tr><td><a href="/facts/Atopic_dermatitis/DvmdVwWu">Atopic Dermatitis</a></td></tr><tr><td><a href="/facts/Rosacea/jxYUX2ml">Rosacea</a></td></tr><tr><td><a href="/facts/Chronic_urticaria/zMkVo9qL">Chronic Urticaria</a></td></tr></tbody></table> <h4>Cancers</h4> <p>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.<a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a> 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.<a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a><a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a><a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a><a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a> In particular, TAZ overexpression conferred resistance to <a href="/facts/Cisplatin/eXLc7Fzw">cisplatin</a> <a href="/facts/Chemotherapy/fWTLbaUT">chemotherapy</a> as well as <a href="/facts/Immunotherapy/hgq3KQaJ">immunotherapy</a> treatment with a <a href="/facts/PD-1_and_PD-L1_inhibitors/M3c1XA0E">PD-1 antibody</a>.<a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a> </p> <table><tbody><tr><th colspan="4">WWTR1 Protein Expression By Cancer Type (from Protein Atlas)</th></tr><tr><th>Cancer Type</th><th># Samples with Medium/High Expression</th><th>Total # Patient Samples</th><th>% Patient Samples with Medium/High Expression</th></tr><tr><td>Glioma</td><td>11</td><td>11</td><td>100%</td></tr><tr><td>Thyroid</td><td>4</td><td>4</td><td>100%</td></tr><tr><td>Lung</td><td>12</td><td>12</td><td>100%</td></tr><tr><td>Colorectal</td><td>11</td><td>11</td><td>100%</td></tr><tr><td>Head and Neck</td><td>4</td><td>4</td><td>100%</td></tr><tr><td>Liver</td><td>12</td><td>12</td><td>100%</td></tr><tr><td>Carcinoid</td><td>4</td><td>4</td><td>100%</td></tr><tr><td>Pancreatic</td><td>9</td><td>9</td><td>100%</td></tr><tr><td>Urothelial</td><td>9</td><td>9</td><td>100%</td></tr><tr><td>Prostate</td><td>10</td><td>10</td><td>100%</td></tr><tr><td>Testis</td><td>11</td><td>11</td><td>100%</td></tr><tr><td>Breast</td><td>12</td><td>12</td><td>100%</td></tr><tr><td>Cervical</td><td>9</td><td>9</td><td>100%</td></tr><tr><td>Endometrial</td><td>10</td><td>10</td><td>100%</td></tr><tr><td>Ovarian</td><td>11</td><td>11</td><td>100%</td></tr><tr><td>Melanoma</td><td>12</td><td>12</td><td>100%</td></tr><tr><td>Skin</td><td>11</td><td>11</td><td>100%</td></tr><tr><td>Stomach</td><td>10</td><td>11</td><td>90.1%</td></tr><tr><td>Renal</td><td>10</td><td>11</td><td>90.1%</td></tr><tr><td>Lymphoma</td><td>9</td><td>12</td><td>75%</td></tr></tbody></table> <h3>As a drug target</h3> <p>YAP and TAZ function have been targeted in several therapeutic methods in the treatment of cancers. </p><p>The Hippo signaling <a href="/facts/Agonist/nz8U5NNp">agonist</a>, C19, increases the phosphorylation of MST1/2 and LATS1/2, resulting in more downstream inactivation of YAP/TAZ. Modulating <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular matrix</a> stiffness and tension using <a href="/facts/Thiazovivin/LvLPQIAb">thiazovivin</a>, <a href="/facts/Cucurbitacin/yV7khyKc">cucurbitacin I</a>, <a href="/facts/Dasatinib/UyTuqLea">dasatinib</a>, <a href="/facts/Fluvastatin/tH55UdPj">fluvastatin</a>, and <a href="/facts/Pazopanib/MtEWoEM1">pazopanib</a>, exhibited positive results in breast cancer cell lines by preventing YAP/WWTR1 translocation to the nucleus.<a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a> 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.<a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a> The class of <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> inhibitors, <a href="/facts/Statin/ba4mes9W">statins</a>, was shown to inhibit the <a href="/facts/Rho_family_of_GTPases/RvAaNbp3">Rho family of GTP-ases (Rho-GTPase)</a>, which are <a href="/facts/Enzyme/DSI1Fh7y">enzymes</a> that signal for upstream inhibition of the Hippo pathway, and exhibited similar effects in attenuating growth of breast cancer and human <a href="/facts/Lung_adenocarcinoma/LHLv9CmQ">lung adenocarcinoma</a> cells.<a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> Statins inhibit <a href="/facts/HMG-CoA_reductase/F6xSdUIt">3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase)</a>, which is the precursor to <a href="/facts/Mevalonate/XLRDojFU">mevalonate</a> in the <a href="/facts/Mevalonate_pathway/uHea16r2">mevalonate pathway</a> that synthesizes the <a href="/facts/Lipid/TdQR87HX">lipid</a> building blocks that form cholesterols and the lipid chains responsible for anchoring Rho-GTPases to the cell membrane.<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a> The Rho-GTPase, <a href="/facts/Transforming_protein_RhoA/qurgmh7r">Ras Family Homolog A (RhoA)</a>, is activated by <a href="/facts/Prenylation/M8owTu4H">prenlylation</a> (the <a href="/facts/Post-translational_modification/KMUayTIc">posttranslational modification</a> through addition of <a href="/facts/Hydrophobe/Ifya0CXQ">hydrophobic groups</a>), and is responsible in part for modulating <a href="/facts/Cytoskeleton/1sWlJRX9">cytoskeletal elements</a> that reduce Hippo pathway activity.<a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a> 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.<a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a><a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a> <a href="/facts/Tyrosine_kinase/26Ln0qJ4">Tyrosine kinases</a> signal in proliferative pathways, some which promote YAP/TAZ function, such as <a href="/facts/Src_family_kinase/8lo52x37">Src family kinases</a> 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.<a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a> </p><p>Inhibition of YAP/TAZ function by targeting their interactions with their transcriptional partners in the TEAD family has also been studied.<a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a><a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a> This includes the use of <a href="/facts/Verteporfin/XI4S22IM">verteporfin</a>, which was investigated in the treatment of skin cancers, particularly melanoma, although it was not taken beyond preclinical studies.<a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a> </p> <table><tbody><tr><th>Drug/Molecule Name</th><th>Drug Class</th><th>Mechanism of Action</th></tr><tr><td>C19</td><td>Hippo kinase agonist</td><td>Increases phosphorylation by MST1/2 and LATS1/2 to inactivate YAP/TAZ and decrease cell proliferation<a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a></td></tr><tr><td><a href="/facts/Dihydrexidine/1H9ewY2E">Dihydrexidine</a></td><td>Dopamine agonist</td><td>Increases LATS1/2 activity; Decreases YAP/TAZ function and cell proliferation<a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a></td></tr><tr><td><a href="/facts/Epinephrine/k7vvMI7E">Epinephrine</a></td><td>Hormonal factor</td><td rowspan="2">Increases LATS1/2 activity; Decreases YAP/TAZ function and cell proliferation<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a></td></tr><tr><td><a href="/facts/Glucagon/NVEnH03n">Glucagon</a></td><td>Hormonal factor</td></tr><tr><td><a href="/facts/Thiazovivin/LvLPQIAb">Thiazovivin</a></td><td>Rho kinase inhibitor</td><td rowspan="5">Inhibits Rho-GTPase; Increases LATS1/2 activity; Decreases YAP/TAZ function and cell proliferation<a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a><a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a></td></tr><tr><td><a href="/facts/Cucurbitacin/yV7khyKc">Cucurbitacin I</a></td><td>JAK/STAT3 inhibitor</td></tr><tr><td><a href="/facts/Dasatinib/UyTuqLea">Dasatinib</a></td><td>Tyrosine kinase inhibitor</td></tr><tr><td><a href="/facts/Fluvastatin/tH55UdPj">Fluvastatin</a></td><td>Statin</td></tr><tr><td><a href="/facts/Pazopanib/MtEWoEM1">Pazopanib</a></td><td>Tyrosine kinase inhibitor</td></tr><tr><td><a href="/facts/Verteporfin/XI4S22IM">Verteporfin</a></td><td>TEAD inhibitor</td><td>Inhibits the binding of YAP/TAZ to TEAD family transcription factors; Decreases proliferative transcription and cell proliferation<a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a></td></tr></tbody></table> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, et al. 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