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Beta-Arrestin-1-Dependent Activation of Extracellular Signal-Regulated Kinases in RON Receptor-Mediated Tumorigenic Activities in Colon Cancer Cells

Author(s): Yong-Qing Zhou | Yu-Lan Luo | Wendy Zhou | Hang-Ping Yao | Ming-Hai Wang

Journal: Journal of Cancer Molecules
ISSN 1816-0735

Volume: 5;
Issue: 2;
Start page: 55;
Date: 2010;
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Keywords: RON | RON160 | β-arrestin-1 | signal transduction | tumorigenic phenotype

AIM: Beta-Arrestin-1 is an adaptor protein essential in G-protein-coupled receptor signaling and function. Recently, a mechanism by which beta-arrestin-1 acted as a scaffolding molecule that regulated signaling pathways of receptor tyrosine kinases was discovered. The goal of this study is to determine the roles of beta-arrestin-1 in RON-activated MAP kinase signaling that regulates tumorigenic activities of colon cancer cells. METHODS: Immunohistochemistry of tumor tissue arrays was used to determine RON and beta-arrestin-1 expression. Immunoprecipitation and Western blotting were used to determine protein interaction and phosphorylation. Specific siRNA was used to silence beta-arrestin-1 gene expression. Cell growth, transformation, and migration were determined by proliferation, focus formation and migration assays. RESULTS: Overexpression of RON (52/88 cases, 59.1%) in primary colon cancer samples was significantly matched with beta-arrestin-1 expression. In 52 samples with RON overexpression, beta-arrestin-1 was co-expressed in 41 cases (46.6%). In colon cancer HT-29 and other cells, beta-arrestin-1 formed a signaling protein complex with RON and c-Src. RON-mediated dephosphorylation of beta-arrestin-1 at Ser-412 increased their interaction. Silencing of beta-arrestin-1 gene expression by siRNA techniques impaired RON-mediated Erk1/2 phosphorylation but had no effect on AKT phosphorylation. The beta-arrestin-1 gene disruption also blocked oncogenic RON160-mediated cellular transformation in rodent fibroblast and colonic epithelial cells. Moreover, silencing beta-arrestin-1 gene expression significantly reduced RON agonistic mAb Zt/c1-induced colon cancer cell proliferation but not migration. CONCLUSION: Beta-Arrestin-1 was selectively involved in RON-transduced signals. The requirement of beta-arrestin-1 in MAP kinase signaling shed light on the mechanisms by which RON regulated malignancy of colon cancer cells.
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