Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling

Hergovich, Alexander; Hemmings, Brian A.

doi:10.1002/biof.47

Cited by 72 publications

(83 citation statements)

References 74 publications

(218 reference statements)

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“…Activated LATS1/2 phosphorylate YAP, which inhibited cell proliferation in mammalian cells 38, 39, 40. In confirmation that WWC2 activates the Hippo pathway in HCC, overexpression of WWC2 in SMMC‐7721 cells (which express low levels of WWC2) increased phosphorylation of both LATS and YAP, which has been previously shown to negatively regulate the Hippo pathway 11, 41, 42. The latter study also revealed HCC cells transfected with the WWC2 overexpression plasmid decreased the mRNA level of Cyr61 and CTGF, both which are the target genes of Hippo pathway.…”

Section: Discussionmentioning

confidence: 57%

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

Zhang

Yan

Chen

et al. 2017

J Cellular Molecular Medi

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WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes‐associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC). Retrospective analysis revealed WWC2 was significantly down‐regulated in 95 clinical HCC tissues compared to the paired adjacent non‐cancerous tissues. Moreover, loss of WWC2 expression was significantly associated with advanced clinicopathological features, including venous infiltration, larger tumour size and advanced TNM stage. Positive WWC2 expression was associated with significantly better 5‐year overall survival, and WWC2 was an independent prognostic factor for overall survival in HCC. Moreover, we confirmed WWC2 inhibits HCC cell invasive ability in vitro. Elevated YAP expression was also observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated WWC2 expression correlated inversely with nuclear YAP protein expression in HCC. Mechanistically, we confirmed overexpression of WWC2 suppresses the invasive and metastatic potential of HCC cells by activating large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co‐activator YAP. Overall, this study indicates WWC2 functions as a tumour suppressor by negatively regulating the Hippo signalling pathway and may serve as a prognostic marker in HCC.

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Section: Discussionmentioning

confidence: 57%

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

Zhang

Yan

Chen

et al. 2017

J Cellular Molecular Medi

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“…Considering that all core components of MEN/SIN and Hippo signalling are conserved from yeast to humans [15,16,73], one might expect that research has already established that a signalling cascade composed of MST1/2 kinases (the human counterpart of Hippo), LATS/ NDR kinases (the human analogues of Lats/Trc), and hMOB1 (the human version of Mats) is essential for mitotic exit and cytokinesis. However, somewhat similar to our current picture of mitotic Hippo signalling in Drosophila (see Section 4), our understanding of mammalian Hippo signalling in mitosis is limited (Fig.…”

Section: Mammalian Hippo Signalling In the G2/m Phase Of The Cell Cyclementioning

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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“…Merlin, Mst1/2, and LATS1/2) or oncogenes (e.g. YAP and its paralog TAZ) (for detailed reviews, see references [22,[26][27][28][29][30][171][172][173]). Together, these studies strongly suggest that dysregulation of size control may be important in the development of human cancers.…”

Section: Cancermentioning

confidence: 99%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.

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Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling

Cited by 72 publications

References 74 publications

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

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

Molecular mechanism of size control in development and human diseases

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