Noncanonical WNT-5A signaling regulates TGF-beta-induced extracellular matrix production by airway smooth muscle cells

Kumawat, K. and Menzen, M. H. and Bos, I. S. and Baarsma, H. A. and Borger, P. and Roth, M. and Tamm, M. and Halayko, A. J. and Simoons, M. and Prins, A. and Postma, D. S. and Schmidt, M. and Gosens, R.. (2013) Noncanonical WNT-5A signaling regulates TGF-beta-induced extracellular matrix production by airway smooth muscle cells. The FASEB journal, Vol. 27, H. 4. pp. 1631-1643.

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Official URL: http://edoc.unibas.ch/dok/A6338072

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Transforming growth factor beta (TGF-beta), a key mediator of fibrotic responses, is increased in asthma and drives airway remodeling by inducing expression of extracellular matrix (ECM) proteins. We investigated the molecular mechanisms underlying TGF-beta-induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF-beta and Wingless/integrase 1 (WNT) signaling in ECM deposition. Airway smooth muscle expresses abundant WNT ligands, with the noncanonical WNT-5A being the most profoundly expressed. Interestingly, WNT-5A shows approximately 2-fold higher abundance in airway smooth muscle cells isolated from individuals with asthma than individuals without asthma. WNT-5A is markedly induced in response to TGF-beta (4-16-fold; EC(5)(0) 0.3 ng/ml) and is required for collagen and fibronectin expression by airway smooth muscle. WNT-5A engages noncanonical WNT signaling pathways, as inhibition of Ca(2+) and c-Jun N-terminal kinase (JNK) signaling attenuated this TGF-beta response, whereas the canonical WNT antagonist Dickkopf 1 (DKK-1) did not. Accordingly, WNT-5A induced JNK phosphorylation and nuclear translocation of nuclear factor of activated T cells c1 (NFATc1). Furthermore, silencing of the WNT-5A receptors Frizzled 8 (FZD8) and RYK attenuated TGF-beta-induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT-5A signaling is activated by and necessary for TGF-beta-induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Pulmonary Cell Research (Roth/Tamm)
UniBasel Contributors:Tamm, Michael and Roth-Chiarello, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Mar 2015 07:44
Deposited On:06 Mar 2015 07:44

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