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

• Xin Hong ^[3] ; Hung Thanh Nguyen ^[4] ; Qingfeng Chen ^[1] ; Rui Zhang ^[5] ; Zandra Hagman ^[2] ; P Mathijs Voorhoeve ^[4] ; Stephen M Cohen ^[3]
  1. [1] Institute of Molecular and Cell Biology

     Institute of Molecular and Cell Biology

     Singapur

     
  2. [2] University of Copenhagen

     University of Copenhagen

     Dinamarca

     
  3. [3] 1 Institute of Molecular and Cell Biology Singapore City, Singapore; 2 Department of Biological Sciences, National University of Singapore Singapore City, Singapore
  4. [4] 3 Duke-NUS Graduate Medical School Singapore City, Singapore
  5. [5] 5 Department of Genetics, Stanford University Palo Alto, CA, USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 21, 2014, págs. 2447-2457
• Idioma: inglés
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  • 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.