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KIBRA Exhibits MST-independent Functional Regulation of the Hippo Signaling Pathway in Mammals

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Author(s)

Susan Moleirinho, Nicole Chang, Andrew Sims, Andrew Martin Tilston-Lunel, Liselotte Angus, Andrew Steele, Vaila Boswell, Susan Barnett, Christopher Ormandy, Dana Faratian, Frank J Gunn-Moore, Paul Andrew Reynolds

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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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Original languageEnglish
Pages (from-to)1821-1830
Number of pages10
JournalOncogene
Volume32
Issue number14
Early online date21 May 2012
DOIs
Publication statusPublished - 2013

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