Axin pathway activity regulates in vivo pY654-?-catenin accumulation and pulmonary fibrosis.

ABSTRACT: Epithelial to mesenchymal transition (EMT) and pulmonary fibrogenesis require epithelial integrin ?3?1-mediated cross-talk between TGF?1 and Wnt signaling pathways. One hallmark of this cross-talk is pY654-?-catenin accumulation, but whether pY654-?-catenin is a biomarker of fibrogenesis or functionally important is unknown. To clarify further the role of ?-catenin in fibrosis, we explored pY654-?-catenin generation and function. ?3?1 was required for TGF?1-mediated activation of Src family kinases, and Src inhibition blocked both pY654 and EMT in primary alveolar epithelial cells (AECs). TGF?1 stimulated ?-catenin/Lef1-dependent promoter activity comparably in immortalized AECs stably expressing WT ?-catenin as well as Y654E or Y654F ?-catenin point mutants. But EMT was abrogated in the Tyr to Phe mutant. pY654-?-catenin was sensitive to the axin ?-catenin turnover pathway as inhibition of tankyrase 1 led to high AEC axin levels, loss of pY654-?-catenin, and inhibition of EMT ex vivo. Mice given a tankyrase inhibitor (50 mg/kg orally) daily for 7 days beginning 10 days after intratracheal bleomycin had improved survival over controls. Treated mice developed raised axin levels in the lung that abrogated pY654-?-catenin and attenuated lung Snail1, Twist1, ?-smooth muscle actin, and type I collagen accumulation. Total ?-catenin levels were unaltered. These findings identify Src kinase(s) as a mediator of TGF?1-induced pY654-?-catenin, provide evidence that pY654-?-catenin levels are a critical determinant of EMT and fibrogenesis, and suggest regulation of axin levels as a novel therapeutic approach to fibrotic disorders.

SUBMITTER: Ulsamer A 

PROVIDER: S-EPMC3281604 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature