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 is an 85 kDa soluble protein from an mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop codon leading to the formation of a RON variant consisting of the entire 35 kDa α-chain and a 45 kDa partial extracellular β-chain. The protein was featured by a sema domain, a hinge motif and a portion of the first IPT unit (designated as RONΔ85). RONΔ85 binds directly to MSP, forms MSP-RONΔ85 complex, and inhibits RON phosphorylation. RONΔ85 disrupts RON or RONΔ160 dimerization, prevents their phosphorylation, and attenuates downstream signaling events. The action of RONΔ85 is specific to RON and has no effect on MET and EGFR. In colon and pancreatic cancer cells, RONΔ85 inhibits spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RONΔ85 also inhibits spontaneous and MSP-induced cell migration. We conclude that RONΔ85 is an antagonist to the MSP-RON pathway, which has potential for regulating RON/RON160-mediated tumorigenic activities.

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