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

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

^* To whom correspondence should be addressed. E-mail: cheng.du{at}umassmed.edu.

	Abstract

-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 -catenin at Thr¹¹² and Thr¹²⁰ residues in vitro and in vivo; mutation of Thr¹¹² and Thr¹²⁰ results in increased nuclear localization of -catenin and is associated with altered -catenin–mediated transcription activity. It is known that mutation of Thr¹²⁰ residue abolishes binding of -catenin to -catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr¹²⁰ could be critical for cell-cell adhesion. Overexpression of PKD1 represses -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–-catenin interaction provides a novel strategy to target -catenin function in cells including prostate cancer. [Cancer Res 2009;69(3):OF1–8]

Key Words: -catenin, E-cadherin, PKD1, phosphorylation, transcription activity

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