The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun; Nishina, Hiroshi

doi:10.1016/j.bbrc.2013.12.100

Cited by 67 publications

(58 citation statements)

References 18 publications

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“…YAP’s PDZ binding motif is necessary for YAP nuclear localization due to its interaction with the tight junction protein zonula occludens 2 (ZO-2)29. Accordingly, in previous work, we demonstrated that YAP (5SA/ΔPDZ) mutant protein is mainly located in the cytoplasm30. In this study, we showed that the percentage of YAP (5SA/ΔPDZ) cells that underwent apical extrusion when surrounded by normal cells was profoundly suppressed compared with that of YAP (5SA) cells, but slightly increased compared with YAP (WT) cells (Fig.…”

Section: Discussionmentioning

confidence: 94%

MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status

Chiba

Ishihara

Miyamura

et al. 2016

Sci Rep

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Cell competition is a cell-cell interaction by which a cell compares its fitness to that of neighboring cells. The cell with the relatively lower fitness level is the “loser” and actively eliminated, while the cell with the relatively higher fitness level is the “winner” and survives. Recent studies have shown that cells with high Yes-associated protein (YAP) activity win cell competitions but the mechanism is unknown. Here, we report the unexpected finding that cells overexpressing constitutively active YAP undergo apical extrusion and are losers, rather than winners, in competitions with normal mammalian epithelial cells. Inhibitors of metabolism-related proteins such as phosphoinositide-3-kinase (PI3K), mammalian target of rapamycin (mTOR), or p70S6 kinase (p70S6K) suppressed this apical extrusion, as did knockdown of vimentin or filamin in neighboring cells. Interestingly, YAP-overexpressing cells switched from losers to winners when co-cultured with cells expressing K-Ras (G12V) or v-Src. Thus, the role of YAP in deciding cell competitions depends on metabolic factors and the status of neighboring cells.

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Section: Discussionmentioning

confidence: 94%

MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status

Chiba

Ishihara

Miyamura

et al. 2016

Sci Rep

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“…Cysteine-rich 61 (Cyr61), one of the tissue growth factors in the CCN family (Cyr61/CTGF/NOV), is highly expressed in various cancer tissues and cell lines, including breast cancer, endometrial cancer, MCF-7 cells, SKOV-3 cells, gastric cancer cells, benign prostatic hyperplasia, gliomas, and melanomas (Lee et al, 2012). Connective tissue growth factor (CTGF), also known as CCN2 has important roles in cell adhesion, migration, proliferation and angiogenesis and was recently shown that the PDZ binding motif of YAP is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity (Shimomura et al, 2014). In addition VEGF expression has been shown in the past that may be also controlled by TEAD via interaction with the Vestigial-like (Vgll) transcription coactivators (Teng et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation

Brodowska

Al-Moujahed

Marmalidou

et al. 2014

Experimental Eye Research

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Verteporfin (VP), a benzoporphyrin derivative, is clinically used in photodynamic therapy for neovascular macular degeneration. Recent studies indicate that VP may inhibit growth of hepatoma cells without photoactivation hrough inhibition of YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human retinoblastoma cell lines. Verteporfin but not vehicle control inhibited the growth, proliferation and viability of human retinoblastoma cell lines (Y79 and WERI) in a dose-dependent manner and was associated with downregulation of YAP-TEAD associated downstream proto-oncogenes such as c-myc, axl, and surviving. In addition VP affected signals involved in cell migration and angiogenesis such as CTGF, cyr61, and VEGF-A but was not associated with significant effect on the mTOR/autophagy pathway. Of interest the pluripotency marker Oct4 were downregulated by Verteporfin treatment. Our results indicate that the clinically used photosensitizer VP is a potent inhibitor of cell growth in retinoblastoma cells, disrupting YAPTEAD signaling and pluripotential marker OCT4. This study highlights for the first time the role of the YAP-TEAD pathway in Retinoblastoma and suggests that VP may be a useful adjuvant therapeutic tool in treating Rb patients.

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“…The expression plasmids for TEAD2 (pCMV-FLAG-TEAD2) and TEAD3 (pCMV-FLAG-TEAD3) were purchased from OriGene Technologies (Rockville, MD). The expression plasmids for hemagglutinin (HA)-tagged TEAD4 (pCMV-HA-TEAD4), myc-tagged YAP (pCMVmyc-YAP), myc-tagged 5SA (pCMV-myc-5SA), and myc-tagged 5SA/TEAD* (pCMV-myc-5SA/TEAD*) were described previously (40).…”

Section: Methodsmentioning

confidence: 99%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.

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The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

Cited by 67 publications

References 18 publications

MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status

MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status

The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

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