title: MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation.
abstract: Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Fukuoka, Japan.|Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Otsubo
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Goto
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Fukuoka, Japan.|Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yanagi
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Nishie
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maehama
authors.affiliation: Department of Developmental and Regenerative Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nishina
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mimori
authors.affiliation: Department of Pathology, Medical School and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: The Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Fukuoka, Japan.|Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C432417:MOB1 protein, mouse; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse