Protein Kinase D1-Mediated Phosphorylation and Subcellular Localization of β-Catenin
Protein Kinase D1-Mediated Phosphorylation and Subcellular Localization of β-Catenin
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DOI：
10.1158/0008-5472.can-07-6270
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Balaji, K. C.
中科院分区：
文献类型：
--
作者：
Du, Cheng;Jaggi, Meena;Balaji, K. C.
β-连环蛋白对于上皮细胞中 E-钙粘蛋白介导的细胞粘附至关重要，并且也是转录活性的关键辅助因子。我们之前表明，信号转导蛋白 PKD 家族的创始成员蛋白激酶 D1 (PKD1) 在晚期前列腺癌中表达下调，并与 E-钙粘蛋白相互作用。这项研究提供了证据，证明 PKD1 在体外和体内与 Thr(112) 和 Thr(120) 残基上的 β-连环蛋白相互作用并磷酸化。 Thr(112) 和 Thr(120) 突变导致 β-连环蛋白核定位增加，并与 β-连环蛋白介导的转录活性改变相关。已知 Thr(120) 残基的突变会消除 β-连环蛋白与 α-连环蛋白的结合，而 α-连环蛋白与细胞骨架相连，这表明 Thr(120) 的 PKD1 磷酸化可能对细胞间粘附至关重要。 PKD1 的过度表达会抑制 β-连环蛋白介导的转录活性和细胞增殖。上位研究表明 PKD1 和 E-钙粘蛋白位于同一信号通路内。了解 PKD1-β-连环蛋白相互作用的分子基础为靶向包括前列腺癌在内的细胞中的 β-连环蛋白功能提供了一种新策略。 [癌症研究 2009；69(3):1117-24]
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. [Cancer Res 2009;69(3):1117-24]