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Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP

Oncogene volume 31, pages 238–250 (2012)Cite this article

Abstract

The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The Drosophila melanogaster protein Expanded acts in the Hippo signaling pathway to control organ size. Previously, willin/FRMD6 has been proposed as the human orthologue of Expanded. Willin lacks C-terminal sequences that are present in Expanded and, to date, little is known about the functional role of willin in mammalian cells. When willin is expressed in D. melanogaster epithelial tissues, it has the same subcellular localization as Expanded, but cannot rescue growth defects associated with expanded deficiency. However, we show that ectopic willin expression causes an increase in phosphorylation of the core Hippo signaling pathway components MST1/2, LATS1 and YAP, an effect that can be antagonized by ezrin. In MCF10A cells, loss of willin expression displays epithelial-to-mesenchymal transition features and willin overexpression antagonizes YAP activity via the N-terminal FERM domain of willin. Therefore, in mammalian cells willin influences Hippo signaling activity by activating the core Hippo pathway kinase cassette.

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Acknowledgements

We thank P Burke for embryo injections and N Chang for technical assistance. We also thank the BBSRC and EPSRC for funding to LA; Scottish University Life Science Alliance for funding to SM. KFH holds Career Development Awards from the International Human Frontier Science Program Organization and the National Health and Medical Research Council of Australia and a Project Grant from the National Health and Medical Research Council of Australia. AS holds Melbourne International Research and Fee Remission Scholarships.

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Author notes

  1. P A Reynolds and F J Gunn-Moore: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Biology, University of St Andrews, St Andrews, UK

    L Angus, S Moleirinho, L Herron & F J Gunn-Moore

  2. School of Medicine, University of St Andrews, St Andrews, UK

    S Moleirinho, M Niestrata & P A Reynolds

  3. Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    A Sinha, X Zhang & K F Harvey

  4. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

    A Sinha, X Zhang & K F Harvey

  5. School of Physics and Astronomy, University of St Andrews, St Andrews, UK

    K Dholakia

  6. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA

    M B Prystowsky

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  1. L Angus
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  2. S Moleirinho
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Correspondence to F J Gunn-Moore.

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Angus, L., Moleirinho, S., Herron, L. et al. Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP. Oncogene 31, 238–250 (2012). https://doi.org/10.1038/onc.2011.224

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