alpha-Catenin overrides Src-dependent activation of beta-catenin oncogenic signaling

Mol Cancer Ther. 2008 Jun;7(6):1386-97. doi: 10.1158/1535-7163.MCT-07-2029.


Loss of alpha-catenin is one of the characteristics of prostate cancer. The catenins (alpha and beta) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of beta-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where beta-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, beta-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of beta-catenin invariably are altered in cancer. Although a wealth of information is available about beta-catenin deregulation during oncogenesis, much less is known about how or whether alpha-catenin regulates beta-catenin functions. In this study, we show that alpha-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of beta-catenin. In alpha-catenin-null prostate cancer cells, reexpression of alpha-catenin increased cell-cell adhesion and decreased beta-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of beta-catenin is a major mechanism for decreased beta-catenin interaction with E-cadherin in alpha-catenin-null cells. alpha-Catenin attenuated the effect of Src phosphorylation by increasing beta-catenin association with E-cadherin. We also show that alpha-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that alpha-catenin is a key regulator of beta-catenin transcriptional activity and that the status of alpha-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cell Proliferation
  • Cyclin D1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Junctions / metabolism
  • Intercellular Junctions / ultrastructure
  • Male
  • Oncogene Proteins / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Signal Transduction*
  • Transcription, Genetic
  • alpha Catenin / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • Oncogene Proteins
  • alpha Catenin
  • beta Catenin
  • Cyclin D1
  • Proto-Oncogene Proteins pp60(c-src)