TGF-β-Activated Kinase 1 (TAK1) Signaling Regulates TGF-β-Induced WNT-5A Expression in Airway Smooth Muscle Cells via Sp1 and β-Catenin

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.

Recruitment of β-Catenin to N-Cadherin Is Necessary for Smooth Muscle Contraction

“…␤-Catenin has also been implicated in regulating the TGF-␤-regulated gene expression in airway smooth muscle cells (47). TGF-␤ was not present under our experimental conditions, and, therefore, the effects of ␤-catenin knockdown or mutant expression on TGF-␤-regulated gene expression was minimal in these cells/tissues.…”

TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms

“…1b, c) suggest that signaling defects in these cells may also have an impact on ciliary length control. Both TGF-β and HH signaling have been shown to regulate the expression of the gene encoding the non-canonical WNT ligand, WNT5A [65–67], which is known to control ciliary length by inducing disassembly of the primary cilium [65, 66, 68, 69]. We therefore hypothesized that Wnt5a expression in Tsc1 − / − MEFs is compromised as a result of low Gli2 expression.…”

Increased Expression of Colonic Wnt9A through Sp1-mediated Transcriptional Effects involving Arylsulfatase B, Chondroitin 4-Sulfate, and Galectin-3

“…Future studies will clarify whether or not the interactions of ARSB, C4S, and galectin-3 also influence effects of Sp3 or Sp4 on Wnt9A transcription, or on transcription of other Wnt family members, in colonic epithelium and in other tissues. Sp1 has also been associated with activation of WNT5A, both in human embryonic tissues and in airway smooth muscle cells following stimulation by TGF-␤ (60,61).…”