A SPLICING VARIANT OF THE RON TRANSCRIPT INDUCES CONSTITUTIVE TYROSINE KINASE-ACTIVITY AND AN INVASIVE PHENOTYPE

The Ron tyrosine kinase receptor shares with the members of its subfam ily (Met and Sea) a unique functional feature: the control of cell dis sociation, motility, and invasion of extracellular matrices (scatterin g), The mature Ron protein is a heterodimer of disulfide-linked alpha and beta chains, originated by proteolytic cleavage of a single-chain precursor of 185 kDa. In a human gastric cancer cell line (KATO-III), we found abnormal accumulation of an uncleaved single-chain protein (D elta-Ron) of 165 kDa; this molecule is encoded by a transcript differi ng from the full-length RON mRNA by an in-frame deletion of 49 amino a cids in the beta-chain extracellular domain, The deleted transcript or iginates by an alternatively spliced cassette exon of 147 bp, flanked by two short introns, The Delta-Ron tyrosine kinase is constitutively activated by disulfide-linked intracellular oligomerization because it contains an uneven number of cysteine residues, Oligomerization and c onstitutive tyrosine phosphorylation of the full-size Ron was obtained by site-directed mutagenesis of a single cysteine residue in the regi on encoded by the cassette exon, mimicking that occurring in the Delta -Ron isoform. Inhibition of thiol-mediated intermolecular disulfide ba nding prevented Delta-Ron oligomerization. The intracellular activatio n of Ron is followed by acquisition of invasive properties in vitro. T hese data (i) provide a novel molecular mechanism for posttranscriptio nal activation of a tyrosine kinase receptor protein and (ii) suggest a role for the Ron receptor in progression toward malignancy.