title: Viral small T oncoproteins transform cells by alleviating hippo-pathway-mediated inhibition of the YAP proto-oncogene.
abstract: Primary human cells can be transformed into tumor cells by a defined set of genetic alterations including telomerase, oncogenic Ras(V12), and the tumor suppressors p53 and pRb. SV40 small T (ST) is required for anchorage-independent growth in vitro and in vivo. Here, we identify the Hippo tumor suppressor pathway as a critical target of ST in cellular transformation. We report that ST uncouples YAP from the inhibitory activity of the Hippo pathway through PAK1-mediated inactivation of NF2. Membrane-tethered activated PAK is sufficient to bypass the requirement for ST in anchorage-independent growth. PAK acts via YAP to mediate the transforming effects of ST. Activation of endogenous YAP is required for ST-mediated transformation and is sufficient to bypass ST in anchorage-independent growth and xenograft tumor formation. Our findings uncover the Hippo tumor suppressor pathway as a final gatekeeper to transformation and tumorigenesis of primary cells.
authors.affiliation: Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Hung Thanh
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.affiliation: Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Sam
authors.initials: S
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore; Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research and Technology (SMART) and Department of Microbiology, National University of Singapore, Singapore 117545, Singapore.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Lifang
authors.initials: L
authors.lastname: Chan
authors.affiliation: Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Department of Physiology, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Marc
authors.initials: M
authors.lastname: Fivaz
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address: scohen@imcb.a-star.edu.sg.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cohen
authors.affiliation: Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: P Mathijs
authors.initials: PM
authors.lastname: Voorhoeve
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002472:Cell Transformation, Viral; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming; C000715470:MAS1 protein, human; D025581:Neurofibromin 2; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases