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

FASEB J. 2013 Aug;27(8):3100-12. doi: 10.1096/fj.12-222620. Epub 2013 May 2.

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.

Keywords: EMT; Wnt signaling; fibronectin; β-integrin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Blotting, Western
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Female
  • GTP-Binding Proteins
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / metabolism
  • Microscopy, Confocal
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Transglutaminases / genetics*
  • Transglutaminases / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism

Substances

  • Integrins
  • Proto-Oncogene Proteins c-myc
  • beta Catenin
  • Cyclin D1
  • transglutaminase 2
  • Transglutaminases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • GTP-Binding Proteins