TGF-β-activated kinase 1 (TAK1) signaling regulates TGF-β-induced WNT-5A expression in airway smooth muscle cells via Sp1 and β-catenin

Kuldeep Kumawat*, Mark H Menzen, Ralph M Slegtenhorst, Andrew J Halayko, Martina Schmidt, Reinoud Gosens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)
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Abstract

WNT-5A, a key player in embryonic development and post-natal homeostasis, has been associated with a myriad of pathological conditions including malignant, fibroproliferative and inflammatory disorders. Previously, we have identified WNT-5A as a transcriptional target of TGF-β in airway smooth muscle cells and demonstrated its function as a mediator of airway remodeling. Here, we investigated the molecular mechanisms underlying TGF-β-induced WNT-5A expression. We show that TGF-β-activated kinase 1 (TAK1) is a critical mediator of WNT-5A expression as its pharmacological inhibition or siRNA-mediated silencing reduced TGF-β induction of WNT-5A. Furthermore, we show that TAK1 engages p38 and c-Jun N-terminal kinase (JNK) signaling which redundantly participates in WNT-5A induction as only simultaneous, but not individual, inhibition of p38 and JNK suppressed TGF-β-induced WNT-5A expression. Remarkably, we demonstrate a central role of β-catenin in TGF-β-induced WNT-5A expression. Regulated by TAK1, β-catenin is required for WNT-5A induction as its silencing repressed WNT-5A expression whereas a constitutively active mutant augmented basal WNT-5A abundance. Furthermore, we identify Sp1 as the transcription factor for WNT-5A and demonstrate its interaction with β-catenin. We discover that Sp1 is recruited to the WNT-5A promoter in a TGF-β-induced and TAK1-regulated manner. Collectively, our findings describe a TAK1-dependent, β-catenin- and Sp1-mediated signaling cascade activated downstream of TGF-β which regulates WNT-5A induction.

Original languageEnglish
Article numbere94801
Number of pages16
JournalPLoS ONE
Volume9
Issue number4
DOIs
Publication statusPublished - 11-Apr-2014

Keywords

  • EXTRACELLULAR-MATRIX PRODUCTION
  • IDIOPATHIC PULMONARY-FIBROSIS
  • GLYCOGEN-SYNTHASE KINASE-3
  • NF-KAPPA-B
  • TRANSCRIPTION FACTOR
  • GENE-TRANSCRIPTION
  • SMAD PATHWAYS
  • STEM-CELLS
  • WNT5A
  • CANCER

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