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

Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusett 01655, USA.
Cancer Research (Impact Factor: 9.28). 02/2009; 69(3):1117-24. DOI: 10.1158/0008-5472.CAN-07-6270
Source: PubMed

ABSTRACT beta-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 beta-catenin at Thr(112) and Thr(120) residues in vitro and in vivo; mutation of Thr(112) and Thr(120) results in increased nuclear localization of beta-catenin and is associated with altered beta-catenin-mediated transcription activity. It is known that mutation of Thr(120) residue abolishes binding of beta-catenin to alpha-catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr(120) could be critical for cell-cell adhesion. Overexpression of PKD1 represses beta-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-beta-catenin interaction provides a novel strategy to target beta-catenin function in cells including prostate cancer.

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    • "These docking interactions may serve two functions. First, by tethering or orienting protein substrates on the enzyme, they may facilitate phosphorylation of sites that do not conform to optimal consensus phosphorylation motifs (perhaps explaining the known effects of PKD1 to phosphorylate sites in c-Jun, ␤-catenin, c-TnI, and type II␣ phosphatidylinositol 4-phosphate kinase that do not conform to LxRxxpS/T motifs) (Hinchliffe and Irvine, 2006; Qin et al., 2006; Waldron et al., 2007; Du et al., 2009). Second, a docking interaction with a protein substrate or scaffold may influence inhibitor sensitivity ; there is recent evidence that PKC is rendered insensitive to inhibitors that compete with ATP when anchored to AKAP79 (Hoshi et al., 2010). "
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    • "Hsp27 mediates repression of AR by PKD1 in PC cells S Hassan et al mutagenesis of T120 and/or T112 decreases b-catenin transcriptional activity (Du et al., 2009). Although the effect of T120 or T112 nonphosphorylation mutant on AR activity is not known, PKD1 may influence AR activity through multiple mechanisms, including Hsp27 and b-catenin-mediated pathways. "
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