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

Abstract

B-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 B-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 B-catenin and is associated with altered B-catenin-mediated transcription activity. It is known that mutation of Thr 120 residue abolishes binding of B-catenin to A-catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr 120 could be critical for cell-cell adhesion. Overexpression of PKD1 represses B-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-B-catenin interaction provides a novel strategy to target B-catenin function in cells including prostate cancer.

Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells

“…Hsp27 mediates repression of AR by PKD1 in PC cells S Hassan et al discovery of PKD1-mediated substrate b-catenin, an established co-activator of AR, which may influence AR transcriptional activity after nuclear transport of AR by Hsp27 Du et al, 2009).…”

“…As shown in Figure 2b, bryostatin-1 can induce Hsp27 phosphorylation at Ser82 or PKD1 phosphorylation at Ser916 in LNCaP or C4-2/PKD1 cells, which have high levels of PKD1 expression, but not in C4-2, which has very low PKD1 expression (Jaggi et al, 2007Du et al, 2009). In contrast, PKD1 activator (bryostatin-1) did not phosphorylate Hsp27 at serine 15, which is not a known PKD1 phosphorylation site, indicating the specificity of PKD1-dependent Hsp27 Ser82 phosphorylation in PC cells (data not shown).…”

“…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.…”

“…Earlier studies show that PKD1 has a role in cell growth, gene expression, survival, motility, protein trafficking and lymphocyte biology (Wang, 2006;Jaggi et al, 2007;Du et al, 2009). In intact cells, PKD1 is activated by phorbol esters, bryostatin-1 (a marine-derived macrolactone), G-protein-coupled receptor agonists, such as neurotensin (NT) and bombesin (Bom), and other growth factors (Rozengurt et al, 2005;Evans et al, 2008;Jaggi et al, 2008;Yuan and Rozengurt, 2008).…”

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

“…Interestingly, a phosphorylation of Ecadherin and -catenin (Thr112 and Thr120 by PKD1) can also lead to the opposite effect: to stimulate -catenin/E-cadherin complex formation [341,392,393]. Accordingly, it has been shown that downregulation of PKD1 is associated with advanced prostate cancers [393].…”