title: Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover.
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.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore City, Singapore Department of Biological Sciences, National University of Singapore, Singapore City, Singapore.
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.affiliation: Duke-NUS Graduate Medical School, Singapore City, Singapore.
authors.forename: Hung Thanh
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Institute of Molecular and Cell Biology, Singapore City, Singapore Singapore-MIT Alliance for Research, and Technology, Singapore City, Singapore.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, CA, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Hagman
authors.affiliation: Duke-NUS Graduate Medical School, Singapore City, Singapore.
authors.forename: P Mathijs
authors.initials: PM
authors.lastname: Voorhoeve
authors.affiliation: 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.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics; D000091102:YAP-Signaling Proteins; D044844:beta-Transducin Repeat-Containing Proteins / Q000276:immunology / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C471644:BTRC protein, human; D010750:Phosphoproteins; C408990:SOCS5 protein, human; C473085:SOCS6 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D018631:ras Proteins
keywords: Hippo pathway; RasV12; anchorage independence; primary cell transformation; tumor suppressor