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EMBO J. 2014 Nov 3;33(21):2447-57. doi: 10.15252/embj.201489385. Epub 2014 Sep 1.

Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover.

Author information

1
Institute of Molecular and Cell Biology, Singapore City, Singapore Department of Biological Sciences, National University of Singapore, Singapore City, Singapore.
2
Duke-NUS Graduate Medical School, Singapore City, Singapore.
3
Institute of Molecular and Cell Biology, Singapore City, Singapore Singapore-MIT Alliance for Research, and Technology, Singapore City, Singapore.
4
Department of Genetics, Stanford University, Palo Alto, CA, USA.
5
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
6
Institute of Molecular and Cell Biology, Singapore City, Singapore Department of Biological Sciences, National University of Singapore, Singapore City, Singapore scohen@imcb.a-star.edu.sg.

Abstract

Cancer genomes accumulate numerous genetic and epigenetic modifications. Yet, human cellular transformation can be accomplished by a few genetically defined elements. These elements activate key pathways required to support replicative immortality and anchorage independent growth, a predictor of tumorigenesis in vivo. Here, we provide evidence that the Hippo tumor suppressor pathway is a key barrier to Ras-mediated cellular transformation. The Hippo pathway targets YAP1 for degradation via the βTrCP-SCF ubiquitin ligase complex. In contrast, the Ras pathway acts oppositely, to promote YAP1 stability through downregulation of the ubiquitin ligase complex substrate recognition factors SOCS5/6. Depletion of SOCS5/6 or upregulation of YAP1 can bypass the requirement for oncogenic Ras in anchorage independent growth in vitro and tumor formation in vivo. Through the YAP1 target, Amphiregulin, Ras activates the endogenous EGFR pathway, which is required for transformation. Thus, the oncogenic activity of Ras(V12) depends on its ability to counteract Hippo pathway activity, creating a positive feedback loop, which depends on stabilization of YAP1.

KEYWORDS:

Hippo pathway; RasV12; anchorage independence; primary cell transformation; tumor suppressor

PMID:
25180228
PMCID:
PMC4283404
DOI:
10.15252/embj.201489385
[Indexed for MEDLINE]
Free PMC Article

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