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Abstract: Generation of splice variants in the RON receptor tyrosine kinase facilitates the invasive phenotype of colorectal cancers. Here, we report a new splice variant of RON in the human colorectal cancer cell line HCT116. This variant is encoded by a transcript differing from the full-length RON mRNA by an in-frame deletion of 106 amino acids in the extracellular domain of RON β-chain. The deleted transcript originates by an alternative deletion of exon 2 and exon 3. The molecular weight of this variant is 160kDa. Thus, we named this variant RONΔ160E2E3. This variant is a single-chain protein and expressed in the intracellular compartment. We found that RONΔ160E2E3 had no tyrosine phosphorylation ability, but it has constitutively activated Akt activity in transfected HEK293 epithelial cells. The expression of this variant in HEK293 cells resulted in an increased migratory activity in vitro mediated through the PI-3K/Akt pathway. Our data describes a new splice variant of RON and suggests a novel role for the RON receptor in the progression of metastasis in colorectal cancer. [Copyright &y& Elsevier]