TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

Pefani, Dafni-Eleftheria; Paňková, Daniela; Abraham, Aswin George; Grawenda, Anna M.; Vlahov, Nikola; Scrace, Simon; Neill, Eric O’

doi:10.1016/j.molcel.2016.05.012

Cited by 135 publications

(134 citation statements)

References 49 publications

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“…17 YAP is a transcriptional coactivator that mainly acts in the cell nucleus. 18 Kaplan-Meier analysis, we indicated that nuclear YAP expression in the cancerous tissues correlated positively with lymph node metastasis, which might support the hypothesis that YAP can be used as a potential marker for tumor invasiveness. 23 We examined the expression levels of the WASF1 gene and found that they were downregulated following YAP knockdown In summary, we demonstrated that YAP was overexpressed in OSCC, notably in the nuclear region and that it promoted tumor migration and invasiveness.…”

Section: Discussionsupporting

confidence: 72%

Yes‐associated protein promotes cell migration via activating Wiskott‐Aldrich syndrome protein family member 1 in oral squamous cell carcinoma

Shi

et al. 2019

J Oral Pathology Medicine

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Background: Yes-associated protein (YAP) is a candidate oncogene in various cancers including oral squamous cell carcinoma (OSCC). Our previous study demonstrated that TNF-alpha could inhibit cell proliferation and invasion by YAP phosphorylation in OSCC. However, the role of YAP in OSCC is not yet clear. The objective of the present study was to elucidate the function of YAP in promoting migration in OSCC and to explore the possible mechanism with a novel YAP inhibitor CA3.Methods: A total of 68 OSCC patients were enrolled, and the expression levels of YAP were investigated in tissue specimens by immunohistochemical staining. The inhibitory effects of CA3, a novel inhibitor of YAP, were demonstrated by immunofluorescence, Western blotting, and transwell assays. A human PCR motility array was performed to screen the changes in the gene expression profiles of the cells. In addition, shRNA interference, YAP re-expression, and WAVE1 overexpression plasmids were used to detect the regulatory mechanism of YAP and its relationship with cell migration.Results: Yes-associated protein nuclear expression levels were associated with metastasis and 5-year overall survival rate. CA3 exhibited potent inhibitory effects on OSCC migration. YAP knockdown significantly suppressed tumor cell migration in OSCC. These effects were rescued when YAP was re-expressed and during WAVE1 overexpression in YAP-shRNA stable cells. Conclusions:The present study revealed that YAP was associated with cell migration and that this process was regulated by YAP/WAVE1. We also demonstrated that CA3 exhibited marked inhibitory effects on YAP expression and that it could be considered a potential therapeutic target for the treatment of OSCC. K E Y W O R D Smigration, oral squamous cell carcinoma, WAVE1, yes-associated protein | 291 QI et al.

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Section: Discussionsupporting

confidence: 72%

Yes‐associated protein promotes cell migration via activating Wiskott‐Aldrich syndrome protein family member 1 in oral squamous cell carcinoma

Shi

et al. 2019

J Oral Pathology Medicine

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“…RASSF1A is one of the most commonly epigenetically inactivated genes in human malignancies. RASSF1A CpG island methylation has been shown to correlate with early cancer onset in several tumour types including lung cancer (Grawenda et al , ; Pefani et al , ). We and others have shown that RASSF1A inactivation results in genomic instability and increased radio‐sensitivity (Dote et al , ; Yee et al , ; Pefani et al , ).…”

Section: Discussionmentioning

confidence: 99%

MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B

et al. 2018

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The heavily transcribed rDNA repeats that give rise to the ribosomal RNA are clustered in a unique chromatin structure, the nucleolus. Due to its highly repetitive nature and transcriptional activity, the nucleolus is considered a hotspot of genomic instability. Breaks in rDNA induce a transient transcriptional shut down to conserve energy and promote rDNA repair; however, how nucleolar chromatin is modified and impacts on rDNA repair is unknown. Here, we uncover that phosphorylation of serine 14 on histone H2B marks transcriptionally inactive nucleolar chromatin in response to DNA damage. We identified that the MST2 kinase localises at the nucleoli and targets phosphorylation of H2BS14p in an ATM‐dependent manner. We show that establishment of H2BS14p is necessary for damage‐induced rDNA transcriptional shut down and maintenance of genomic integrity. Ablation of MST2 kinase, or upstream activators, results in defective establishment of nucleolar H2BS14p, perturbed DNA damage repair, sensitisation to rDNA damage and increased cell lethality. We highlight the impact of chromatin regulation in the rDNA damage response and targeting of the nucleolus as an emerging cancer therapeutic approach.

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“…Interactions between Hippo and TGF-β signaling pathways has been shown in recent years15161718. YAP is a key component of the Hippo pathway, which functions as a transcriptional co-activator.…”

mentioning

confidence: 99%

YAP modulates TGF-β1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor

Liu

Ying

et al. 2017

Sci Rep

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YAP is a transcriptional co-regulator that plays important roles in various patho-physiological processes, including the survival and death of cells. However, the effect of YAP on apoptosis and EMT, simultaneously mediated by TGF-β1, is not known. In this study, we demonstrate that YAP can modulate cell fate of apoptosis versus EMT by acting as a surviving factor. Overexpression of YAP in mouse mammary epithelial (NMuMG) cells suppressed TGF-β1-induced apoptosis, which shifted the cellular response predominantly toward EMT. In contrast, knockdown of YAP induced spontaneous apoptosis and enhanced TGF-β1-induced apoptosis, leading to a sharp decrease in the proportion of surviving cells that underwent EMT. These data suggest that YAP is an essential factor for modulating cellular responses to TGF-β1. Further investigation showed that YAP could regulate the expression level and activation of EGFR. Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis, whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP. The results indicate that EGFR and its activation are critical for YAP-mediated suppression of TGF-β1-induced apoptosis. This study provides a new understanding of the regulatory mechanism underlying the determination of cell fate in response to TGF-β1-mediated simultaneous apoptosis and EMT.

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TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

Cited by 135 publications

References 49 publications

Yes‐associated protein promotes cell migration via activating Wiskott‐Aldrich syndrome protein family member 1 in oral squamous cell carcinoma

Yes‐associated protein promotes cell migration via activating Wiskott‐Aldrich syndrome protein family member 1 in oral squamous cell carcinoma

MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B

YAP modulates TGF-β1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor

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