Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation
Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation
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DOI：
10.1128/mcb.00758-14
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发表时间：
2014-10-01
影响因子：
5.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Arimoto, Kei-ichiro;Burkart, Christoph;Zhang, Dong-Er
表皮生长因子（EGF）受体（EGFR）与肿瘤的发生和侵袭有关。EGFR的二聚化和自身磷酸化是EGFR活化的关键事件。然而，EGF依赖性和EGF非依赖性的EGFR二聚化和磷酸化的调节尚未完全了解。在这里，我们报告，细胞质蛋白plakophilin-2（PKP 2）是一种新的EGFR信号的正调控。PKP 2通过其N-末端头部结构域与EGFR特异性相互作用。增加PKP 2表达增强EGF依赖性和EGF非依赖性EGFR二聚化和磷酸化。此外，PKP 2敲低降低EGFR磷酸化并减弱EGFR介导的信号激活，导致癌细胞增殖和迁移以及肿瘤发展的显著降低。我们的研究结果表明PKP 2是EGFR信号通路的一种新激活剂，也是一种潜在的抑制肿瘤生长的新药物靶点。
Epidermal growth factor (EGF) receptor (EGFR) has been implicated in tumor development and invasion. Dimerization and autophosphorylation of EGFR are the critical events for EGFR activation. However, the regulation of EGF-dependent and EGF-independent dimerization and phosphorylation of EGFR has not been fully understood. Here, we report that cytoplasmic protein plakophilin-2 (PKP2) is a novel positive regulator of EGFR signaling. PKP2 specifically interacts with EGFR via its N-terminal head domain. Increased PKP2 expression enhances EGF-dependent and EGF-independent EGFR dimerization and phosphorylation. Moreover, PKP2 knockdown reduces EGFR phosphorylation and attenuates EGFR-mediated signal activation, resulting in a significant decrease in proliferation and migration of cancer cells and tumor development. Our results indicate that PKP2 is a novel activator of the EGFR signaling pathway and a potential new drug target for inhibiting tumor growth.