Hung Thanh Nguyen1,*, Xin Hong2,3*, Sam Tan1, Qingfeng Chen2,4, Lifang Chan1, Marc Fivaz1,5, Stephen M. Cohen2,3 & P. Mathijs Voorhoeve1.
1 Duke-NUS Graduate Medical School, 8 College Rd, Singapore,169857
2 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore, 138673
3 Department of Biological Sciences, National University of Singapore, 117543
4 Department of Microbiology, National University of Singapore, 117545
5 Department of Physiology, National University of Singapore, 117597
* Equal contribution
Published in Cell Reports on 31 July 2014.
Primary human cells can be transformed into tumor cells by a defined set of genetic alterations including telomerase, oncogenic RasV12 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 Small T in anchorage-independent growth. PAK acts via YAP to mediate the transforming effects of Small T. Activation of endogenous YAP mediates the transforming effects of Small T, and is sufficient to bypass Small T 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.
- Small T acts via PAK to inactivate NF2 tumor suppressor thereby activating YAP
- PAK acts downstream of ST in cellular transformation
- YAP is required for anchorage independent growth caused by Small T and active PAK1
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