title: 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.
authors.affiliation: Medical and Biological Sciences Building, School of Medicine, University of St Andrews, St Andrews, UK.
authors.forename: S
authors.initials: S
authors.lastname: Moleirinho
authors.forename: N
authors.initials: N
authors.lastname: Chang
authors.forename: A H
authors.initials: AH
authors.lastname: Sims
authors.forename: A M
authors.initials: AM
authors.lastname: Tilston-Lünel
authors.forename: L
authors.initials: L
authors.lastname: Angus
authors.forename: A
authors.initials: A
authors.lastname: Steele
authors.forename: V
authors.initials: V
authors.lastname: Boswell
authors.forename: S C
authors.initials: SC
authors.lastname: Barnett
authors.forename: C
authors.initials: C
authors.lastname: Ormandy
authors.forename: D
authors.initials: D
authors.lastname: Faratian
authors.forename: F J
authors.initials: FJ
authors.lastname: Gunn-Moore
authors.forename: P A
authors.initials: PA
authors.lastname: Reynolds
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D062445:Claudin-1; D003598:Cytoskeletal Proteins; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; C568108:CLDN1 protein, human; C504793:FRMD6 protein, human; C513637:WWC1 protein, human; C456659:YY1AP1 protein, human; C082332:macrophage stimulating protein; C092745:LATS1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases