Mechanisms of YAP/TAZ transcriptional control

Battilana, Giusy; Zanconato, Francesca; Piccolo, Stefano

doi:10.15698/cst2021.11.258

Cited by 27 publications

(31 citation statements)

References 28 publications

(50 reference statements)

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“…Another variation of the GAL4-based assay is that it can be used to isolate compounds that specifically inhibit YAP-transcriptional activity. Since YAP can also interact with transcription factors other than TEAD1–4, TEAD inhibitors may not completely block YAP activity [ 2 , 3 ]. It is, therefore, desirable to develop compounds to specifically inhibit interaction of the YAP-transcriptional activation domain (TAD) with its cognate partners.…”

Section: Assays For High Throughput Screeningmentioning

confidence: 99%

“…Phosphorylated YAP/TAZ becomes sequestered in the cytoplasm by interacting with 14-3-3 proteins. Hypo/unphosphorylated YAP/TAZ translocate into the nucleus and associate with TEAD1-4 transcription factors to regulate the expression of a large number of target genes [ 2 , 3 ]. Many of the YAP target genes encode matricellular proteins that promote cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers

Maity

Gridnev

Misra

2022

Cancers

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YAP/TAZ are transcriptional coactivators that function as the key downstream effectors of Hippo signaling. They are commonly misregulated in most human cancers, which exhibit a higher level of expression and nuclear localization of YAP/TAZ, and display addiction to YAP-dependent transcription. In the nucleus, these coactivators associate with TEA domain transcription factors (TEAD1-4) to regulate the expression of genes that promote cell proliferation and inhibit cell death. Together, this results in an excessive growth of the cancerous tissue. Further, YAP/TAZ play a critical role in tumor metastasis and chemotherapy resistance by promoting cancer stem cell fate. Furthermore, they affect tumor immunity by promoting the expression of PD-L1. Thus, YAP plays an important role in multiple aspects of cancer biology and thus, provides a critical target for cancer therapy. Here we discuss various assays that are used for conducting high-throughput screens of small molecule libraries for hit identification, and subsequent hit validation for successful discovery of potent inhibitors of YAP-transcriptional activity. Furthermore, we describe the advantages and limitations of these assays.

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Section: Assays For High Throughput Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers

Maity

Gridnev

Misra

2022

Cancers

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“…Our findings that Rab40c regulates MOB1 protein levels and phosphorylation prompted us to test whether Hippo downstream transcription factors YAP and TAZ are also activated, because LATS1/MOB1 complex mediates YAP/TAZ phosphorylation ( Meng et al, 2016 ; Battilana et al, 2021 ). Phosphorylation of YAP/TAZ acts as a negative regulator of YAP/TAZ by keeping them in cytosol and away from the nucleus ( Rausch & Hansen, 2020 ; Kwon et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation

et al. 2022

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Rab40c is a SOCS box–containing protein which binds Cullin5 to form a ubiquitin E3 ligase complex (Rab40c/CRL5) to regulate protein ubiquitylation. However, the exact functions of Rab40c remain to be determined, and what proteins are the targets of Rab40c-Cullin5–mediated ubiquitylation in mammalian cells are unknown. Here we showed that in migrating MDA-MB-231 cells Rab40c regulates focal adhesion’s number, size, and distribution. Mechanistically, we found that Rab40c binds the protein phosphatase 6 (PP6) complex and ubiquitylates one of its subunits, ankyrin repeat domain 28 (ANKRD28), thus leading to its lysosomal degradation. Furthermore, we identified that phosphorylation of FAK and MOB1 is decreased in Rab40c knock-out cells, which may contribute to focal adhesion site regulation by Rab40c. Thus, we propose a model where Rab40c/CRL5 regulates ANKRD28 ubiquitylation and degradation, leading to a decrease in PP6 activity, which ultimately affects FAK and Hippo pathway signaling to alter focal adhesion dynamics.

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“…In recent years, hippo signaling in many human cancer types has been studied which provides a better understanding of their role in cancer progression. Targeting the YAP/TAZ transcriptional network chemical inhibitors might be a significant step forward in the combat against cancer therapy resistance 49 . The nuclear-cytoplasmic shuttling of YAP/TAZ has been given considerable attention for its regulatory function 50 .…”

Section: Discussionmentioning

confidence: 99%

Platycodin D confers oxaliplatin Resistance in Colorectal Cancer by activating the LATS2/YAP1 axis of the hippo signaling pathway

Wang¹,

Baskaran²,

Ng³

et al. 2023

J. Cancer

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Oxaliplatin-based therapy is used as a first-line drug to treat metastatic colorectal cancer. However, long-term and repeated drug treatment resulted in drug resistance and the failure of chemotherapy. Various natural compounds were previously reported to act as chemosensitizers to reverse drug resistance. In this study, we found that platycodin D (PD), a saponin found in Platycodon grandiflorum, inhibited LoVo and OR-LoVo cells proliferation, invasion, and migration ability. Our results indicated that combined treatment of oxaliplatin with PD dramatically reduced the cellular proliferation in both LoVo and OR-LoVo cells. Furthermore, treatment with PD dose-dependently decreased LATS2/YAP1 hippo signaling and survival marker p-AKT expression, as well as increased cyclin-dependent kinase inhibitor proteins such as p21 and p27 expression. Importantly, PD activates and promotes YAP1 degradation through the ubiquitination and proteasome pathway. The nuclear transactivation of YAP was significantly reduced under PD treatment, leading to transcriptional inhibition of the downstream genes regulating cell proliferation, pro-survival, and metastasis. In conclusion, our results showed that PD is suitable as a promising agent for overcoming oxaliplatin-resistant colorectal cancer.

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Mechanisms of YAP/TAZ transcriptional control

Cited by 27 publications

References 28 publications

Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers

Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers

Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation

Platycodin D confers oxaliplatin Resistance in Colorectal Cancer by activating the LATS2/YAP1 axis of the hippo signaling pathway

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