Protein kinase D1-mediated phosphorylation and subcellular localization of beta-catenin.
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.
Du
Cheng
C
Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusett 01655, USA. cheng.du@umassmed.edu
Jaggi
Meena
M
Zhang
Chuanyou
C
Balaji
K C
KC
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D050396:TRPP Cation Channels / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D011493:Protein Kinase C; D050396:TRPP Cation Channels; D051176:beta Catenin; C089212:protein kinase D