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

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-beta in airway smooth muscle cells and demonstrated its function as a mediator of airway remodeling. Here, we investigated the molecular mechanisms underlying TGF-beta-induced WNT-5A expression. We show that TGF-beta-activated kinase 1 (TAK1) is a critical mediator of WNT-5A expression as its pharmacological inhibition or siRNA-mediated silencing reduced TGF-beta 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-beta-induced WNT-5A expression. Remarkably, we demonstrate a central role of beta-catenin in TGF-beta-induced WNT-5A expression. Regulated by TAK1, beta-catenin is required for WNT-5A induction as it 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 beta-catenin. We discover that Sp1 is recruited to the WNT-5A promoter in a TGF-beta-induced and TAK1-regulated manner. Collectively, our findings describe a TAK1-dependent, beta-catenin- and Sp1-mediated signaling cascade activated downstream of TGF-beta which regulates WNT-5A induction.