Tissue transglutaminase regulates ?-catenin signaling through a c-Src-dependent mechanism.

ABSTRACT: Tissue transglutaminase (TG2) is a multifunctional enzyme involved in protein cross-linking and cell adhesion to fibronectin (FN). In cancer, TG2 induces an epithelial to mesenchymal transition, contributing to metastasis. Because cadherins bind ?-catenin at cell-cell junctions, disruption of adherens junctions destabilizes cadherin-catenin complexes. The goal of the present study was to analyze whether and how TG2 interacts with and regulates ?-catenin signaling in ovarian cancer (OC) cells. We observed a significant correlation between TG2 and ?-catenin expression levels in OC cells and tumors. TG2 augmented Wnt/?-catenin signaling, as evidenced by enhanced ?-catenin transcriptional activity, inducing transcription of target genes cyclin D1 and c-Myc. By promoting integrin-mediated cell adhesion to FN, TG2 physically associates with and recruits c-Src, which in turn phosphorylates ?-catenin at Tyr(654), releasing it from E-cadherin and rendering it available for transcriptional regulation. By interacting with FN and enhancing ?-catenin signaling, complexed TG2 stimulates OC cell proliferation. In summary, our data demonstrate that TG2 regulates ?-catenin expression and function in OC cells and define the c-Src-dependent mechanism through which this occurs.

SUBMITTER: Condello S 

PROVIDER: S-EPMC4050431 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature