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Cancer Res. 2009 Feb 1;69(3):1117-24. doi: 10.1158/0008-5472.CAN-07-6270. Epub 2009 Jan 13.

Protein kinase D1-mediated phosphorylation and subcellular localization of beta-catenin.

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  • 1Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusett 01655, USA. cheng.du@umassmed.edu

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.

PMID:
19141652
DOI:
10.1158/0008-5472.CAN-07-6270
[PubMed - indexed for MEDLINE]
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