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J. Biol. Chem., Vol. 280, Issue 26, 25087-25094, July 1, 2005

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Mechanisms of Cytoplasmic -Catenin Accumulation and Its Involvement in Tumorigenic Activities Mediated by Oncogenic Splicing Variant of the Receptor Originated from Nantes Tyrosine Kinase^*

Xiang-Ming Xu, Yong-Qing Zhou¶, and Ming-Hai Wang||

From the Laboratory of Cheung Kong Scholars Program for Biomedical Sciences at Institute of Infectious Diseases and ^¶Division of Neurosurgery, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, People's Republic of China and Department of Pharmaceutical Sciences and Center for Biology of Cancer, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas 79106

The -catenin pathway plays a critical role in the pathogenesis of certain types of cancers. To gain insight into mechanisms by which altered receptor tyrosine kinases regulate cytoplasmic -catenin accumulation, the effect of an oncogenic receptor originated from Nantes (RON) variant on -catenin accumulation and the role of -catenin in RON-mediated tumorigenic activities were studied. In NIH3T3 cells harboring oncogenic variant RON160, increased -catenin accumulation with tyrosine phosphorylation and nuclear translocation was observed. Overexpression of RON160 also resulted in increased expression of -catenin target genes c-myc and cyclin D1. By analyzing cellular proteins that regulate -catenin stabilities, it was found that RON160 activates the protein disheveled (DVL) and inactivates glycogen synthase kinase-3 by Ser-9 residue phosphorylation. These effects were channeled by RON160-activated PI 3-kinase-AKT pathways that are sensitive to specific inhibitors, such as wortmannin, but not to other chemical inhibitors. Silencing RON160 expression by specific small interfering RNA blocked not only -catenin expression but also c-myc and cyclin D1 expression, suggesting that RON expression is required for the activation of the -catenin signaling pathway. Moreover, it was found that knockdown of the -catenin gene expression by small interfering RNA techniques reduces significantly the RON160-mediated NIH3T3 cell proliferation, focus-forming activities and anchorage-independent growth. Thus, the oncogenic RON variant regulates -catenin stabilities through activation of DVL and inactivation of glycogen synthase kinase-3. The activated -catenin cascade is one of the pathways involved in tumorigenic activities mediated by the oncogenic RON variant.

Received for publication, December 30, 2004 , and in revised form, March 17, 2005.

^* This work was supported by grants from the National Institutes of Health (R01 CA91980), National Science Foundation of China (NSFC-3043700), and by funds from the Amarillo Area Foundation and Cheung Kong Scholars Program Foundation of the Chinese Ministry of Education. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pharmaceutical Sciences and Ctr. for Biology of Cancer, Texas Tech University Health Sciences Ctr. School of Pharmacy, 1300 S. Coulter St., Amarillo, TX 79106. Tel.: 806-356-4015 (ext. 248); Fax: 806-356-4034; E-mail: minghai.wang{at}ttuhsc.edu.

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