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Opposing activities of the R as and H ippo pathways converge on regulation of YAP protein turnover
Author(s) -
Hong Xin,
Nguyen Hung Thanh,
Chen Qingfeng,
Zhang Rui,
Hagman Zandra,
Voorhoeve P Mathijs,
Cohen Stephen M
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489385
Subject(s) - library science , zhàng , alliance , sociology , biology , political science , china , law , computer science
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 YAP 1 stability through downregulation of the ubiquitin ligase complex substrate recognition factors SOCS 5/6. Depletion of SOCS 5/6 or upregulation of YAP 1 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 YAP 1.