title: Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP.
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.
authors.affiliation: School of Biology, University of St Andrews, St Andrews, UK.
authors.forename: L
authors.initials: L
authors.lastname: Angus
authors.forename: S
authors.initials: S
authors.lastname: Moleirinho
authors.forename: L
authors.initials: L
authors.lastname: Herron
authors.forename: A
authors.initials: A
authors.lastname: Sinha
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Niestrata
authors.forename: K
authors.initials: K
authors.lastname: Dholakia
authors.forename: M B
authors.initials: MB
authors.lastname: Prystowsky
authors.forename: K F
authors.initials: KF
authors.lastname: Harvey
authors.forename: P A
authors.initials: PA
authors.lastname: Reynolds
authors.forename: F J
authors.initials: FJ
authors.lastname: Gunn-Moore
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004331:Drosophila melanogaster; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D009857:Oncogenes; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C504793:FRMD6 protein, human; C503814:Yki protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases