Pathological role of the RON receptor tyrosine kinase in colorectal cancer: Characterization of a short-form RON variant

RON is a member of the MET family of receptor tyrosine kinases. When activated by its ligand, macrophage stimulating protein (MSP), RON initiates downstream signaling events that result in cell dissociation, migration, and invasion. Several RON variants that arise through mRNA splicing or by an alternate translational start site have been identified, some with oncogenic potential. The purpose of the present study was to characterize and determine any pathogenic roles of a naturally occurring 52 kD N-terminal truncated RON (sf-RON). Sf-RON was found to be overexpressed in 37% of 35 primary and 30% of 10 metastatic colorectal carcinomas (CRCs). Sf-RON was also expressed and constitutively phosphorylated in three CRC cell lines. Cloning sf-RON from a CRC cell line and transfecting it into AA/C1 colon epithelial cells resulted in constitutive activation with increased Map kinase p44/42 (ERK1/2) phosphorylation. Sf-RON expression also caused a decrease in E-cadherin, an important cell adhesion molecule whose downregulation is associated with poor survival in cancer. These changes in cell signaling were accompanied by a change in cell-shape and increased cellular growth and migration. Taken together, sf-RON may play a role in the progression of CRC to a more malignant phenotype.