alpha-Catenin overrides Src-dependent activation of beta-catenin oncogenic signaling.
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.
Inge
Landon J
LJ
Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, 1701 Rockland Road, Wilmington, DE 19803, USA.
Rajasekaran
Sigrid A
SA
Wolle
Daniel
D
Barwe
Sonali P
SP
Ryazantsev
Sergey
S
Ewing
Charles M
CM
Isaacs
William B
WB
Rajasekaran
Ayyappan K
AK
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051178:alpha Catenin / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015513:Oncogene Proteins; D051178:alpha Catenin; D051176:beta Catenin; D019938:Cyclin D1; D016392:Proto-Oncogene Proteins pp60(c-src)