α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling
Open Access
- 1 June 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 7 (6), 1386-1397
- https://doi.org/10.1158/1535-7163.mct-07-2029
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. [Mol Cancer Ther 2008;7(6):1386–97]Keywords
This publication has 53 references indexed in Scilit:
- ErbB-2 Induces the Cyclin D1 Gene in Prostate Epithelial Cells In vitro and In vivoCancer Research, 2007
- Impact of differential cyclin D1 expression and localisation in prostate cancerBritish Journal of Cancer, 2007
- Cinderella no longer: α-catenin steps out of cadherin's shadowJournal of Cell Science, 2006
- The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulationJournal of Cell Science, 2004
- Expression of α-catenin in α-catenin-deficient cells results in a reduced proliferation in three-dimensional multicellular spheroids but not in two-dimensional monolayer culturesOncogene, 2004
- p120 Catenin-Associated Fer and Fyn Tyrosine Kinases Regulate β-Catenin Tyr-142 Phosphorylation and β-Catenin-α-Catenin InteractionMolecular and Cellular Biology, 2003
- Analysis of β-Catenin Aggregation and Localization Using GFP Fusion Proteins: Nuclear Import of α-Catenin by the β-Catenin/Tcf ComplexExperimental Cell Research, 2000
- Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC −/− Colon CarcinomaScience, 1997
- Cell Adhesion: The Molecular Basis of Tissue Architecture and MorphogenesisCell, 1996
- Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic miceNature, 1994