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

L. Angus, Susana Moleirinho, Lissa Herron, A. Sinha, X. Zhang, M Niestrata, K Dholakia, Michael B Prystowsky, KF Harvey, P.A. Reynolds, FJ Gunn-Moore

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)238-50
Number of pages13
JournalOncogene
Volume31
Issue number2
DOIs
Publication statusPublished - Jan 2012

Keywords

  • Animals
  • Apoptosis
  • Cell Line
  • Cytoskeletal Proteins/metabolism
  • Drosophila Proteins/antagonists & inhibitors
  • Drosophila Proteins/metabolism
  • Drosophila melanogaster
  • Epithelial-Mesenchymal Transition
  • Humans
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Membrane Proteins/metabolism
  • Nuclear Proteins/antagonists & inhibitors
  • Oncogenes
  • Phosphorylation
  • Protein-Serine-Threonine Kinases/metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Subcellular Fractions/metabolism
  • Trans-Activators/antagonists & inhibitors

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