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Research Paper
Blocking Tumorigenic Activities of Colorectal Cancer Cells by a Splicing RON Receptor Variant Defective in the Tyrosine Kinase Domain
Ming-Hai Wang, Wei-Feng Lao, Da Wang, Yu-Lan Luo and Hang-Ping Yao
volume 6 | issue 7
July 2007Pages: 1121 - 1129
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Altered expression of the RON receptor tyrosine kinase, accompanied by generation of splicing variants, contributes to the pathogenesis of epithelial cancers such as invasive growth of colorectal caners. In this study, we have studied a novel RON variant (designated as RONΔ170) that regulates tumorigenic activities of colorectal cancer cells by blocking RON-mediated tumorigenic signals. RONΔ170 is a splicing variant with a deletion of exon 19 that encodes 46 amino acids in the catalytic kinase domain. This deletion also causes a reading-frame shift and creates a new stop codon, which effectively eliminates the multi-functional docking site and truncates the RON C-terminus. As a RON variant without kinase activities and the C-terminal docking domain, RONΔ170 acts as a variant receptor that negatively regulates biochemical and biological activities mediated by RON or its oncogenic variant RONΔ160. In NIH3T3 expressing RONΔ160, RONΔ170 formed a complex with RONΔ160 and prevented RONΔ160-mediated activation of signaling proteins such as Erk1/2 and AKT. These effects resulted in decreased cell proliferation, reduced colony formation, and diminished cell migration. These negative activities were also observed in colorectal cancer cells naturally expressing RON or RONΔ160 including HT-29, HCT116, and SW620. Introduction of RONΔ170 into HCT116 cells blocked MSP-induced Erk1/2 and AKT phosphorylation, reduced cytoplasmic β-catenin accumulation, restored glycogen synthase kinase-3β activity, and attenuated various tumorigenic activities. Moreover, RONΔ170 expression significantly reduced SW620 cell-mediated tumor growth in vivo. Thus, RONΔ170 is a naturally occurring variant with dominant negative activities and has potential for inhibiting RON-mediated tumorigenic activities in colorectal cancer cells.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.