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

Academic Article

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 β-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 β-catenin signaling in ovarian cancer (OC) cells. We observed a significant correlation between TG2 and β-catenin expression levels in OC cells and tumors. TG2 augmented Wnt/β-catenin signaling, as evidenced by enhanced β-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 β-catenin at Tyr(654), releasing it from E-cadherin and rendering it available for transcriptional regulation. By interacting with FN and enhancing β-catenin signaling, complexed TG2 stimulates OC cell proliferation. In summary, our data demonstrate that TG2 regulates β-catenin expression and function in OC cells and define the c-Src-dependent mechanism through which this occurs.
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    Published In

    Keywords

  • EMT, Wnt signaling, fibronectin, β-integrin, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Female, GTP-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Integrins, Microscopy, Confocal, Ovarian Neoplasms, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-myc, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transglutaminases, beta Catenin, src-Family Kinases
  • Digital Object Identifier (doi)

    Author List

  • Condello S; Cao L; Matei D
  • Start Page

  • 3100
  • End Page

  • 3112
  • Volume

  • 27
  • Issue

  • 8