Ianni, Alessandro ORCID: 0000-0001-7398-589X, Hofmann, Michael, Kumari, Poonam, Tarighi, Shahriar, Al-Tamari, Hamza M., Goergens, Andre, Giebel, Bernd, Nolte, Hendrik, Krueger, Marcus, Salwig, Isabelle, Pullamsetti, Soni Savai, Guenther, Andreas, Schneider, Andre and Braun, Thomas (2021). Depletion of Numb and Numblike in Murine Lung Epithelial Cells Ameliorates Bleomycin-Induced Lung Fibrosis by Inhibiting the beta-Catenin Signaling Pathway. Front. Cell. Dev. Biol., 9. LAUSANNE: FRONTIERS MEDIA SA. ISSN 2296-634X

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Abstract

Idiopathic pulmonary fibrosis (IPF) represents the most aggressive form of pulmonary fibrosis (PF) and is a highly debilitating disorder with a poorly understood etiology. The lung epithelium seems to play a critical role in the initiation and progression of the disease. A repeated injury of lung epithelial cells prompts type II alveolar cells to secrete pro-fibrotic cytokines, which induces differentiation of resident mesenchymal stem cells into myofibroblasts, thus promoting aberrant deposition of extracellular matrix (ECM) and formation of fibrotic lesions. Reactivation of developmental pathways such as the Wnt-beta-catenin signaling cascade in lung epithelial cells plays a critical role in this process, but the underlying mechanisms are still enigmatic. Here, we demonstrate that the membrane-associated protein NUMB is required for pathological activation of beta-catenin signaling in lung epithelial cells following bleomycin-induced injury. Importantly, depletion of Numb and Numblike reduces accumulation of fibrotic lesions, preserves lung functions, and increases survival rates after bleomycin treatment of mice. Mechanistically, we demonstrate that NUMB interacts with casein kinase 2 (CK2) and relies on CK2 to activate beta-catenin signaling. We propose that pharmacological inhibition of NUMB signaling may represent an effective strategy for the development of novel therapeutic approaches against PF.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ianni, AlessandroUNSPECIFIEDorcid.org/0000-0001-7398-589XUNSPECIFIED
Hofmann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumari, PoonamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tarighi, ShahriarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Tamari, Hamza M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goergens, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giebel, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salwig, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pullamsetti, Soni SavaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-591316
DOI: 10.3389/fcell.2021.639162
Journal or Publication Title: Front. Cell. Dev. Biol.
Volume: 9
Date: 2021
Publisher: FRONTIERS MEDIA SA
Place of Publication: LAUSANNE
ISSN: 2296-634X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IDIOPATHIC PULMONARY-FIBROSIS; MESENCHYMAL TRANSITION; MOUSE NUMB; RESPIRATORY EPITHELIUM; GENE-EXPRESSION; PROTEIN; DIFFERENTIATION; ACTIVATION; PROLIFERATION; DISINTEGRITYMultiple languages
Cell Biology; Developmental BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59131

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