title: Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells.
abstract: Transforming growth factor β (TGF-β), 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-β-induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF-β 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 ∼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-β (4-16-fold; EC₅₀ 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-β 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-β-induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT-5A signaling is activated by and necessary for TGF-β-induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. k.kumawat@rug.nl
authors.forename: Kuldeep
authors.initials: K
authors.lastname: Kumawat
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.forename: I Sophie T
authors.initials: IS
authors.lastname: Bos
authors.forename: Hoeke A
authors.initials: HA
authors.lastname: Baarsma
authors.forename: Pieter
authors.initials: P
authors.lastname: Borger
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Mirjam
authors.initials: M
authors.lastname: Simoons
authors.forename: Alita
authors.initials: A
authors.lastname: Prins
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D003094:Collagen; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium