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Protein Kinase D1–Mediated Phosphorylation and Subcellular Localization of β-Catenin

¹ Division of Urology, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts and ² Department of Obstetrics and Gynecology and Basic Biomedical Science, Sanford School of Medicine, The University of South Dakota, Sioux Falls, South Dakota

Requests for reprints: Cheng Du or K.C. Balaji, Division of Urology, Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01655. Phone: 508-856-2576; Fax: 508-856-3137; balajik{at}ummhc.org or cheng.du{at}umassmed.edu.

Key Words: β-catenin • E-cadherin • PKD1 • phosphorylation • transcription activity

β-Catenin is essential for E-cadherin–mediated cell adhesion in epithelial cells and also acts as a key cofactor for transcription activity. We previously showed that protein kinase D1 (PKD1), founding member of the PKD family of signal transduction proteins, is down-regulated in advanced prostate cancer and interacts with E-cadherin. This study provides evidence that PKD1 interacts with and phosphorylates β-catenin at Thr¹¹² and Thr¹²⁰ residues in vitro and in vivo; mutation of Thr¹¹² and Thr¹²⁰ results in increased nuclear localization of β-catenin and is associated with altered β-catenin–mediated transcription activity. It is known that mutation of Thr¹²⁰ residue abolishes binding of β-catenin to -catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr¹²⁰ could be critical for cell-cell adhesion. Overexpression of PKD1 represses β-catenin–mediated transcriptional activity and cell proliferation. Epistatic studies suggest that PKD1 and E-cadherin are within the same signaling pathway. Understanding the molecular basis of PKD1–β-catenin interaction provides a novel strategy to target β-catenin function in cells including prostate cancer. [Cancer Res 2009;69(3):1117–24]

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