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KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals

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 upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.

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Acknowledgements

We are very grateful to Dr Avruch for providing the MOBKL1A/B antibody and to Dr Takeichi for providing the Willin antibody. We thank V Fedele and E Campbell for technical assistance. We also thank the Scottish University Life Science Alliance for funding for SM and Breakthrough Breast Cancer for funding for AHS and DF. CJO was funded by The National Health and Medical Research Council of Australia, New South Wales Cancer Council, Cancer Institute New South Wales, Banque Nationale de Paris-Paribas Australia and New Zealand, RT Hall Trust, Australian Cancer Research Foundation and the National Breast Cancer Foundation.

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Correspondence to F J Gunn-Moore or P A Reynolds.

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Moleirinho, S., Chang, N., Sims, A. et al. KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals. Oncogene 32, 1821–1830 (2013). https://doi.org/10.1038/onc.2012.196

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  • DOI: https://doi.org/10.1038/onc.2012.196

Keywords

  • KIBRA
  • Hippo pathway
  • Merlin
  • Willin
  • breast cancer
  • claudin-low

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