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

SUBMITTER: Kumawat K

PROVIDER: S-EPMC3984265 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Kumawat Kuldeep K Menzen Mark H MH Slegtenhorst Ralph M RM Halayko Andrew J AJ Schmidt Martina M Gosens Reinoud R

PloS one 20140411 4

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 ...[more]

PMID: 24728340

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Dataset Information

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

Publications

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

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