Hong, Xin3; Nguyen, Thanh Hung7; Chen, Qingfeng4; Zhang, Rui5; Hagman, Zandra7; Voorhoeve, P Mathijs6; Cohen, Stephen M7
1 Section VI. Building 18.4, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Morphogenesis and Differentiation Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 Institute of Molecular and Cell Biology, Singapore City, Singapore Department of Biological Sciences, National University of Singapore, Singapore City, Singapore.4 Institute of Molecular and Cell Biology, Singapore City, Singapore Singapore-MIT Alliance for Research, and Technology, Singapore City, Singapore.5 Department of Genetics, Stanford University, Palo Alto, CA, USA.6 Duke-NUS Graduate Medical School, Singapore City, Singapore.7 Section VI. Building 18.4, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.
E M B O Journal, 2014, Vol 33, Issue 21, p. 2447-2457