Abstract

Abstract The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON-MSP pathway in various cancer cells. The variant was an 85 kDa soluble protein from a mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop code leading to a RON variant composed of a full 35kDa α-chain and a 45 kDa partial extracellular β-chain. The protein was featured by a sema domain, a hinge and a portion of the first IPT unit (designated as RON 85). RON 85 directly bound to the MSP, formed the MSP-RON 85 complex, and inhibited RON phosphorylation. RON 85 disrupted RON or RON 160 dimerization, prevented their phosphorylation, and attenuated their downstream signaling events. The action of RON 85 was specific to RON and had no effect on MET and EGFR. In colon and pancreatic cancer cells, RON 85 inhibited spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RON 85 also inhibited spontaneous or MSP-induced cell migration. We concluded that RON 85 is an antagonist to the MSP-RON pathway with therapeutic potentials for controlling tumorigenic phenotypes of cancer cells. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B240.

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