The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network

Harvey, Kieran F.; Tapon, Nicolas

doi:10.1038/nrc2070

Cited by 595 publications

(626 citation statements)

References 92 publications

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“…Although cell death was attributed to aberrant regulation of H-Ras, JNK and nuclear factor-kB, PRX-Imediated MST1 activation probably also takes part in this process, and further examinations of these pathways could facilitate the development of better chemotherapeutic agents. Recent studies have indicated the importance of a mammalian signaling pathway equivalent to the Drosophila Hippo pathway in tumor suppression (Harvey and Tapon, 2007;Zeng and Hong, 2008). In Drosophila, Hippo activates Warts (LATS1/2 in mammals) together with Salvador (WW45 in mammals).…”

Section: Discussionmentioning

confidence: 99%

“…Activated Warts then excludes an oncogenic transcription factor Yorkie (YAP in mammals) from the nucleus and induces apoptosis. The Hippo pathway appears to be conserved in mammals, and the human genes for several pathway components have been found to be mutated in cancers (O'Neill et al, 2005;Harvey and Tapon, 2007;Zeng and Hong, 2008). PRX-I is also suggested to suppress cancer development because mice lacking the PRX-I gene have a short life span owing to frequent development of several cancers (Neumann et al, 2003;Egler et al, 2005;Graves et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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Mammalian Ste20-like kinase-1 (MST1) kinase mediates H 2 O 2 -induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H 2 O 2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H 2 O 2 -induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H 2 O 2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H 2 O 2 -induced MST1 activation. Live-cell imaging showed H 2 O 2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H 2 O 2 -induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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“…[1][2][3] In mammals, recent studies have established a role for this pathway in regulating cell contact inhibition, organ size control, and cancer development. [4][5][6] The Hippo pathway is activated upon sensing of cell-cell contact via cell surface molecules.…”

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confidence: 99%

c-Abl antagonizes the YAP oncogenic function

et al. 2014

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YES-associated protein (YAP) is a central transcription coactivator that functions as an oncogene in a number of experimental systems. However, under DNA damage, YAP activates pro-apoptotic genes in conjunction with p73. This program switching is mediated by c-Abl (Abelson murine leukemia viral oncogene) via phosphorylation of YAP at the Y357 residue (pY357). YAP as an oncogene coactivates the TEAD (transcriptional enhancer activator domain) family transcription factors. Here we asked whether c-Abl regulates the YAP-TEAD functional module. We found that DNA damage, through c-Abl activation, specifically depressed YAP-TEAD-induced transcription. Remarkably, c-Abl counteracts YAP-induced transformation by interfering with the YAP-TEAD transcriptional program. c-Abl induced TEAD1 phosphorylation, but the YAP-TEAD complex remained unaffected. In contrast, TEAD coactivation was compromised by phosphomimetic YAP Y357E mutation but not Y357F, as demonstrated at the level of reporter genes and endogenous TEAD target genes. Furthermore, YAP Y357E also severely compromised the role of YAP in cell transformation, migration, anchorage-independent growth, and epithelial-to-mesenchymal transition (EMT) in human mammary MCF10A cells. These results suggest that YAP pY357 lost TEAD transcription activation function. Our results demonstrate that YAP pY357 inactivates YAP oncogenic function and establish a role for YAP Y357 phosphorylation in cell-fate decision.

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“…Over the past decade Ste20-like kinases, MOB proteins, and LATS/NDR kinases have gained even more attention, since Hippo (a GCK-II Ste20-like kinase), Mats/dMOB1, and Warts/Lats (one of two LATS/NDR kinases in flies) have been established as the central signalling module of the Hippo tumour suppressor signalling cascade in Drosophila melanogaster [21][22][23]. Loss of Hippo, Mats or Warts could be functionally compensated by their mammalian counterparts MST2, LATS1 and MOB1A, respectively [24][25][26], strongly suggesting that, similar to the MEN/SIN, Hippo signalling is very highly conserved from flies to humans.…”

Section: Introductionmentioning

confidence: 99%

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hergovich

Hemmings

2012

Seminars in Cell & Developmental Biology

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Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts.

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The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network

Cited by 595 publications

References 92 publications

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

c-Abl antagonizes the YAP oncogenic function

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

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