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Hong, Xin; Nguyen, Hung Thanh; Chen, Qingfeng; Zhang, Rui; Hagman, Zandra; Voorhoeve, P Mathijs; Cohen, Stephen M
The EMBO journal, 3 November 2014, Volume: 33, Issue: 21Journal Article
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 RasV12 depends on its ability to counteract Hippo pathway activity, creating a positive feedback loop, which depends on stabilization of YAP1. Synopsis Ras antagonises Hippo tumor suppressor activity by direct regulation of YAP‐stability. Ras controls SOCS‐protein expression, channeling YAP into ubiquitin‐dependent degradation. YAP expression is sufficient to bypass the role of oncogenic Ras in transformation of primary human cells, and acts via a feedback loop involving Amphiregulin and EGFR. Ras acts via downregulation of SOCS5/6 to reduce YAP protein turnover. By reducing YAP turnover, the Ras pathway acts in opposition to the Hippo tumor suppressor pathway, which promotes YAP turnover. The levels of SOCS6 mRNA and the YAP target AREG were inversely correlated in colorectal cancer with a wild‐type K‐Ras gene, but not in K‐Ras mutant cancers. Ras antagonises Hippo tumor suppressor activity by direct regulation of YAP‐stability. Ras controls SOCS‐protein expression, channeling YAP into ubiquitin‐dependent degradation.
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