J. Cancer Mol. 5: 55-62, 2010
Beta-Arrestin-1-Dependent Activation of Extracellular Signal-Regulated
Kinases in RON Receptor-Mediated Tumorigenic Activities in Colon Cancer
Yong-Qing Zhou, Yu-Lan Luo, Wendy Zhou, Hang-Ping Yao, and Ming-Hai Wang
Laboratory of Cancer Biology & Therapeutics and Division of
Neurosurgery, First Affiliated Hospital, Zhejiang University School of
Medicine, Hangzhou, 310003, P. R. China [Y.-Q. Zhou, H.-P. Yao, M.-H.
Wang]; Cancer Biology Center and Department of Biomedical Sciences,
School of Pharmacy, Texas Tech University Health Sciences Center,
Amarillo, TX 79106, USA [Y.-L. Luo, W. Zhou, M.-H. Wang]
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
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.
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.
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.
RON; RON160; beta-arrestin-1; signal transduction; tumorigenic phenotype)
Received 7/6/09; Revised 9/14/09; Accepted 9/24/09.
Dr. Yong-Qing Zhou, Division of Neurosurgery, First Affiliated
Hospital, Zhejiang University School of Medicine, No. 79 Qing-Chun Road,
Hangzhou, Zhejiang, 310003, P. R. China. E-mail: firstname.lastname@example.org;
Dr. Ming-Hai Wang, Department of Pharmaceutical Sciences, School of
Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX
79106, USA. Phone: 1-806-3564015 ext. 248. Fax: 1-806-3564034. E-mail:
MAP, mitogen-activated protein kinase; Erk, extracellular
signal-regulated kinase; RON, recepteur d¡¦origine nantais; Sos, son of
sevenless; Grb, growth factor receptor bound protein; mAb monoclonal
antibody; siRNA, small interfering RNA; MSP, macrophage-stimulating
protein; PI, phosphatidylinositol; Dvl, protein disheveled; PDGF,
platelet-derived growth factor.
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