title: 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.
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA karimoto@ucsd.edu d7zhang@ucsd.edu.
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Arimoto
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Burkart
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Ran
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weng
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA Department of Pathology and Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA karimoto@ucsd.edu d7zhang@ucsd.edu.
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D051191:Plakophilins / Q000502:physiology*; D055503:Protein Multimerization; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008024:Ligands; D051191:Plakophilins; D018719:Erb-b2 Receptor Tyrosine Kinases; C495337:PKP2 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human
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