TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells

Finch-Edmondson, Megan; Strauss, Robyn P.; Passman, Adam M.; Sudol, Marius; Yeoh, George; Callus, Bernard A.

doi:10.1074/jbc.m115.692285

Cited by 66 publications

(64 citation statements)

References 49 publications

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“…Moreover, the mild observed upregulation of TAZ in YAP-silenced cells was incapable to counteract FA loss46. The apparent discrepancy between YAP and TAZ activities could be explained by the slight but consistent differences in the transcriptional and functional signatures of YAP and TAZ reported here and by others4627. Solving this puzzle deserves further investigations.…”

Section: Discussionmentioning

confidence: 51%

YAP regulates cell mechanics by controlling focal adhesion assembly

et al. 2017

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Hippo effectors YAP/TAZ act as on–off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described by a hierarchical model in which elements of Hippo pathway are under the control of focal adhesions (FAs). Here we unveil the molecular mechanism by which cell spreading and RhoA GTPase activity control FA formation through YAP to stabilize the anchorage of the actin cytoskeleton to the cell membrane. This mechanism requires YAP co-transcriptional function and involves the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity leads to the modification of cell mechanics, force development and adhesion strength, and determines cell shape, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify this Hippo effector as the key determinant of cell mechanics in response to ECM cues.

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Section: Discussionmentioning

confidence: 51%

YAP regulates cell mechanics by controlling focal adhesion assembly

et al. 2017

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“…YAP and TAZ are transcriptional coactivators that function as effectors of the Hippo pathway. To maintain Hippo pathway homeostasis, TAZ accumulation can be negatively regulated by YAP abundance . More recently, Moroishi et al .…”

Section: Resultsmentioning

confidence: 99%

Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway

et al. 2017

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Porphyrin derivatives, in particular verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of the YAP–TEAD interaction and transcriptional activity. Herein we report the efficient convergent synthesis of the dipyrrin half of protoporphyrin IX dimethyl ester (PPIX‐DME), in which the sensitive vinyl group was created at the final stage by a dehydroiodination reaction. Two other dipyrrin derivatives were synthesized, including dipyrrin 19 [(Z)‐2‐((3,5‐dimethyl‐4‐vinyl‐2H‐pyrrol‐2‐ylidene)methyl)‐3,5‐dimethyl‐4‐vinyl‐1H‐pyrrole], containing two vinyl groups. We found that VP and dipyrrin 19 showed significant inhibitory effects on TEAD transcriptional activity in MDA‐MB‐231 human breast cancer cells, whereas other compounds did not show significant changes. In addition, we observed a marked decrease in both YAP and TAZ levels following VP treatment, whereas dipyrrin 19 treatment primarily decreased the levels of YAP and receptor kinase AXL, a downstream target of YAP. Together, our data suggest that, due to their chemical structures, porphyrin‐ and dipyrrin‐related derivatives can directly target YAP and/or TAZ proteins and inhibit TEAD transcriptional activity.

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“…Interestingly, YAP has recently been shown to inversely regulate TAZ protein, but this inverse relationship is unidirectional, only being observed upon modulation of YAP and not TAZ , This inverse relationship extends to skeletal muscle, since overexpression of TAZ mutants in C2C12 myoblasts or knockdown of TAZ in RD cells do not seem to have compensatory effects on YAP in RD cells.…”

Section: Discussionmentioning

confidence: 99%

The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma

Mohamed

Sun

Mello

et al. 2016

The Journal of Pathology

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The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12% of fusion gene‐negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA‐mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage‐independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC–Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T‐box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells

Cited by 66 publications

References 49 publications

YAP regulates cell mechanics by controlling focal adhesion assembly

YAP regulates cell mechanics by controlling focal adhesion assembly

Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway

The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma

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