G protein‐coupled receptors engage the mammalian Hippo pathway through F‐actin

Regué, Laura; Mou, Fan; Avruch, Joseph

doi:10.1002/bies.201200163

Cited by 24 publications

(14 citation statements)

References 61 publications

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“…Activation of several small GTPases, including Ras, Rac1, and Rho1, has been shown to promote F-actin accumulation or Hippo target gene expression ( Reddy and Irvine, 2013 ; Regue et al, 2013 ; Fernandez et al, 2014 ). We investigated whether any of them acted through the p38 pathway.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Hippo signalling by p38 signalling

Huang

Sun

et al. 2016

Journal of Molecular Cell Biology

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The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts. We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation.

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Section: Resultsmentioning

confidence: 99%

Regulation of Hippo signalling by p38 signalling

Huang

Sun

et al. 2016

Journal of Molecular Cell Biology

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“…As a component of the tumour microenvironment, the extracellular matrix has a significant impact on the development, progression, and therapy response in tumours ( Giussani et al, 2015 ; Lu et al, 2012 ). F-actin can relay its effect on YAP through several mechanisms such as G-protein-coupled receptors (GPCRs), which are known to combine the actin cytoskeleton with several signalling pathways (reviewed in Regue et al, 2013 ), or IQGAP1, a scaffold protein known to regulate the F-actin and microtubule network and shown to play a pivotal role in a bile acid-induced liver cancer through YAP ( Anakk et al, 2013 ). Thus, YAP activation not only correlates with increased proliferation but might promote tumour progression through interactions with the tumour environment.…”

Section: Discussionmentioning

confidence: 99%

A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth

Mayrhofer¹,

Gourain²,

Reischl

et al. 2016

Disease Models &Amp; Mechanisms

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Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho (p)-ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA) sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.

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“…Recently, it was shown that Lysophosphatidic Acid (LPA) and Sphingosine 1-Phospophate (S1P) are able to inhibit the Hippo signalling by activating YAP/TAZ transcriptional activity through activation of Gα 12/13 . Moreover, activation of YAP through the Protease Activated Receptor 1 (PAR1) GPCR was shown to act through activation of RHOA, leading to an increased assembly of F-actin (Regué et al, 2013;Yu et al, 2012a). Interestingly, activation of the two transcriptional co-activators YAP and TAZ has also been associated to WNT signalling, where activation of the pathway by WNT-5A/B and WNT-3A leads to the de-phosphorylation of YAP/TAZ and the subsequent activation through FZD/ROR/Gα 12/13 signalling, independent of β-catenin (Park et al, 2015).…”

Section: Gα 12/13 Signallingmentioning

confidence: 99%