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

FASEB J. 2013 Apr;27(4):1631-43. doi: 10.1096/fj.12-217539. Epub 2012 Dec 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Cells, Cultured
  • Collagen / metabolism
  • Extracellular Matrix Proteins / metabolism*
  • Fibronectins / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction* / drug effects
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Wnt Proteins / metabolism*
  • Wnt-5a Protein


  • Extracellular Matrix Proteins
  • Fibronectins
  • Proto-Oncogene Proteins
  • Transforming Growth Factor beta
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • Collagen
  • JNK Mitogen-Activated Protein Kinases
  • Calcium