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Research Articles: Therapeutics, Targets, and Development

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

¹ Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, Wilmington, Delaware; Departments of ² Pathology and Laboratory Medicine and ³ Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California; and ⁴ Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Ayyappan K. Rajasekaran, Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, 1701 Rockland Road, Wilmington, DE 19803. Phone: 302-651-6593; Fax: 302-651-4827. E-mail: araj{at}medsci.udel.edu

Abstract

Loss of -catenin is one of the characteristics of prostate cancer. The catenins ( 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 -catenin regulates β-catenin functions. In this study, we show that -catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of β-catenin. In -catenin-null prostate cancer cells, reexpression of -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 -catenin-null cells. -Catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that -catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that -catenin is a key regulator of β-catenin transcriptional activity and that the status of -catenin expression in tumor tissues might have prognostic value for Src targeted therapy. [Mol Cancer Ther 2008;7(6):1386–97]

Grant support: NIH grants DK 56216, F31-GM068985, and DOD W81XWH-04-1-0113.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 4/07; revised 3/10/08; accepted 3/25/08.