Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Abstract

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.

This article is related to:

Plakophilin-2 Promotes Activation of Epidermal Growth Factor Receptor

ACKNOWLEDGMENTS

We thank Paul S. Mischel and Frank Furnari (Ludwig Institute for Cancer Research, UCSD) and Gen-Sheng Feng (Department of Pathology, UCSD) for critical reading of the manuscript. We thank Kunitada Shimotohno (National Center for Global Health and Medicine, Japan) for plasmid vectors (C-terminally tagged pCAG vector, GST [6p-1], and C-terminally Myc-tagged pcDNA3.1 vector), Jo Minji (Steven Gonias laboratory, UCSD) for MDA-MB-468 cells, and David Cheresh (Moores Cancer Center, UCSD) for MDA-MB-231 cells. We thank all members of the D.-E.Z. laboratory and Keun Il Kim (Sookmyung Women's University, South Korea) for helpful discussion. We also thank Chuyi Cheng and Yue Zhang (Division of Biological Sciences, UCSD) for their technical assistance in this study.

This work was supported by funding from the U.S. National Institutes of Health (R01CA177305 and R01HL091549). Kei-ichiro Arimoto is a Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellow for Research Abroad.