Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer

Wang, Yumeng; Xu, Xiaowu; Maglic, Dejan; Dill, Michael T.; Mojumdar, Kamalika; Ng, Patrick Kwok-Shing; Jeong, Kang Jin; Tsang, Yiu Huen; Moreno, Daniela; Bhavana, Venkata Hemanjani; Peng, Xinxin; Ge, Zhongqi; Hu, Chen; Li, Jun; Chen, Zhongyuan; Zhang, Huiwen; Han, Leng; Du, Di; Creighton, Chad J.; Mills, Gordon B.; Camargo, Fernando D.; Liang, Han

doi:10.1016/j.celrep.2018.10.001

Cited by 358 publications

(357 citation statements)

References 54 publications

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“…Accumulating evidences suggest that dysregulation of the Hippo pathway and hyperactivation of YAP have been frequently associated with various types of human cancers including breast, liver, lung, ovary, colon, kidney, brain and others 8,9,54 . Moreover, recent human cancer genome studies also connected the genetic alteration of the Hippo pathway components with cancer development 55,56 . Given the evolutionarily conserved roles for the Hippo pathway components, it will be interesting to characterize the oncogenic alteration of the Hippo pathway in evolution.…”

Section: Resultsmentioning

confidence: 99%

Systematic analysis of the Hippo pathway organization and oncogenic alteration in evolution

Chen

Han

Seo

et al. 2020

Sci Rep

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the Hippo pathway is a central regulator of organ size and a key tumor suppressor via coordinating cell proliferation and death. initially discovered in Drosophila, the Hippo pathway has been implicated as an evolutionarily conserved pathway in mammals; however, how this pathway was evolved to be functional from its origin is still largely unknown. In this study, we traced the Hippo pathway in premetazoan species, characterized the intrinsic functions of its ancestor components, and unveiled the evolutionary history of this key signaling pathway from its unicellular origin. In addition, we elucidated the paralogous gene history for the mammalian Hippo pathway components and characterized their cancer-derived somatic mutations from an evolutionary perspective. Taken together, our findings not only traced the conserved function of the Hippo pathway to its unicellular ancestor components, but also provided novel evolutionary insights into the Hippo pathway organization and oncogenic alteration.A long-standing question in developmental biology is how metazoan species acquired the ability to precisely control their tissue/organ size 1 . This intriguing phenomenon could be traced to some non-metazoan organisms, since their aggregative behaviors can be similarly regulated 2-4 . Initially discovered in Drosophila, the Hippo pathway is a highly conserved pathway known for its crucial role in organ size control via restricting cell proliferation and inducing apoptosis 5-9 , shedding light on this fundamental question in evolution.In Drosophila, the core components of the Hippo pathway comprise two serine/threonine kinases Hippo 10-14 and Warts 15,16 , adaptor proteins Salvador 17,18 and Mats 19 , a transcriptional co-activator Yorkie 20 and a transcriptional factor Scalloped 21-23 . Together with Salvador, Hippo phosphorylates and activates Warts, which in turn phosphorylates Yorkie 24,25 . Yorkie can shuttle between the cytoplasm and nucleus, a process tightly controlled by the Warts-mediated phosphorylation 24,25 . Upon phosphorylation, Yorkie is recognized by 14-3-3 proteins and sequestered in the cytoplasm 24,25 . When Hippo signaling is inactivated, Yorkie translocates into the nucleus, where it forms a complex with Scalloped to initiate the transcription of genes involved in proliferation and anti-apoptosis, two critical events required for tissue/organ growth. The Hippo/Salvador-Warts/Mats kinase cascade can be regulated by multiple upstream regulators. Among them, Merlin 26 , Kibra 27-29 and Fat 30-32 have been implicated to play conserved roles in the mammalian Hippo pathway. Moreover, Hippo is not absolutely required for the phosphorylation and activation of Warts, since another two serine/threonine kinases Happyhour and Misshapen were also found responsible for Warts activation in both Drosophila and mammals [33][34][35] , highlighting the complexity of the Hippo pathway regulation.Although multiple Hippo pathway-related studies have been carried out in species from Drosophila to mammals for decades, its compone...

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Section: Resultsmentioning

confidence: 99%

Systematic analysis of the Hippo pathway organization and oncogenic alteration in evolution

Chen

Han

Seo

et al. 2020

Sci Rep

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“…Nuclear translocation of YAP1 is regulated by multiple mechanical stimuli, such as matrix stiffness, epithelial stretching and cell density [2][3][4][25][26] . To test the effects of mechanical environment on YAP1 localization, we removed utricles from P15 mice and placed them in Such data suggest that placement in culture leads to temporary YAP1 nuclear translocation, but that nuclear immunoreactivity of YAP1 returned to normal (0 hr time point) levels by 24 hr in vitro ( Fig.…”

Section: Placement In Organotypic Culture Evokes Transient Nuclear Trmentioning

confidence: 99%

“…The Hippo/YAP1 pathway is an evolutionarily conserved signaling network known to be involved in regulating tissue size and cell number during development [2][3][4][25][26] , The transcriptional coactivator YAP1 is the primary effector of Hippo signaling. Under normal conditions, YAP1 is sequestered in the cytoplasm and targeted for degradation.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

Borse

Barton

Arndt

et al. 2020

Preprint

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The Hippo pathway is an evolutionarily conserved signaling pathway involved in regulating organ size, development, homeostasis and regeneration [1][2][3][4] . YAP1 is a transcriptional coactivator and the primary effector of Hippo signaling. Upstream activation of the Hippo pathway leads to nuclear translocation of YAP1, which then evokes changes in gene expression and cell cycle entry 5 . A prior study has demonstrated nuclear translocation of YAP1 in the supporting cells of the developing utricle 6 , but the possible role of YAP1 in hair cell regeneration is unclear. The present study characterizes the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after hair cell injury. During neonatal development of the mouse utricle, YAP1 expression was observed in the cytoplasm ofsupporting cells, and was also transiently expressed in the cytoplasm of hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle at short time periods after placement in organotypic culture. However, little or no nuclear translocation of YAP1 was observed after injury to the utricles of neonatal or mature mice. In contrast, a significant degree of YAP1 nuclear translocation was observed in the chicken utricle after streptomycin-induced hair cell damage in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may be partly responsible for the distinct regenerative abilities of the avian vs. mammalian inner ear.

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“…Focusing only on tumours that have lost merlin function would probably miss meso theliomas in which Hippo signalling is inhibited by inactivation of other proteins, such as LATS1 and LATS2. A previous study 17 of the Hippo pathway in various cancers has revealed that 22 genes are commonly trans cribed by YAP and TAZ, and this transcriptional profile might offer a way to identify ferroptosis-sensitive tumours. Further more, because this profile was found 17 in several types of tumour, triggering ferroptosis might be worth exploring for cancers other than mesothelioma.…”

mentioning

confidence: 98%

Signs that Jupiter was mixed by a giant impact

Guillot¹

2019

Nature

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Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer

Cited by 358 publications

References 54 publications

Systematic analysis of the Hippo pathway organization and oncogenic alteration in evolution

Systematic analysis of the Hippo pathway organization and oncogenic alteration in evolution

Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

Signs that Jupiter was mixed by a giant impact

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