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: K Otsubo, H Goto, M Nishio, K Kawamura, S Yanagi, W Nishie, T Sasaki, T Maehama, H Nishina, K Mimori, T Nakano, H Shimizu, T W Mak, K Nakao, Y Nakanishi, A Suzuki
• Journal: Oncogene (Oncogene) Vol. 36 Issue 29 Pg. 4201-4211 (07 20 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 28346423 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• Intracellular Signaling Peptides and Proteins
• MOB1 protein, mouse
• Nkx2-1 protein, mouse
• Nuclear Proteins
• Phosphoproteins
• Thyroid Nuclear Factor 1
• Trans-Activators
• Transcription Factors
• Wwtr1 protein, mouse
• YAP-Signaling Proteins
• Yap1 protein, mouse
• Acyltransferases
• tafazzin protein, mouse

Topics

• Acyltransferases
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Cell Adhesion (physiology)
• Cell Cycle Proteins
• Cell Differentiation (physiology)
• Cell Line, Tumor
• Humans
• Intracellular Signaling Peptides and Proteins
• Lung Neoplasms (genetics, metabolism, pathology)
• Mice
• Nuclear Proteins (genetics, metabolism)
• Phosphoproteins (genetics, metabolism)
• Signal Transduction
• Thyroid Nuclear Factor 1
• Trans-Activators
• Transcription Factors (genetics, metabolism)
• YAP-Signaling Proteins