α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling

Landon J. Inge, Sigrid A. Rajasekaran, Daniel Wolle, Sonali P. Barwe, Sergey Ryazantsev, Charles M. Ewing, William B. Isaacs, Ayyappan K. Rajasekaran

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)1386-1397
Number of pages12
JournalMolecular cancer therapeutics
Volume7
Issue number6
DOIs
StatePublished - Oct 15 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inge, L. J., Rajasekaran, S. A., Wolle, D., Barwe, S. P., Ryazantsev, S., Ewing, C. M., Isaacs, W. B., & Rajasekaran, A. K. (2008). α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling. Molecular cancer therapeutics, 7(6), 1386-1397. https://doi.org/10.1158/1535-7163.MCT-07-2029