A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype

Chiara Collesi, Massimo M. Santoro, Giovanni Gaudino, Paolo M. Comoglio

Research output: Contribution to journalArticlepeer-review

Abstract

The Ron tyrosine kinase receptor shares with the members of its subfamily (Met and Sea) a unique functional feature: the control of cell dissociation, motility, and invasion of extracellular matrices (scattering). The mature Ron protein is a heterodimer of disulfide-linked α and β 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 (Δ-Ron) of 165 kDa; this molecule is encoded by a transcript differing from the full-length RON mRNA by an in- frame deletion of 49 amino acids in the β-chain extracellular domain. The deleted transcript originates by an alternatively spliced cassette exon of 147 bp, flanked by two short introns. The Δ-Ron tyrosine kinase is constitutively activated by disulfide-linked intracellular oligomerization because it contains an uneven number of cysteine residues. Oligomerization and constitutive tyrosine phosphorylation of the full-size Ron was obtained by site-directed mutagenesis of a single cysteine residue in the region encoded by the cassette exon, mimicking that occurring in the Δ-Ron isoform. Inhibition of thiol-mediated intermolecular disulfide bonding prevented Δ- Ron oligomerization. The intracellular activation of Ron is followed by acquisition of invasive properties in vitro. These data (i) provide a novel molecular mechanism for posttranscriptional activation of a tyrosine kinase receptor protein and (ii) suggest a role for the Ron receptor in progression toward malignancy.

Original languageEnglish
Pages (from-to)5518-5526
Number of pages9
JournalMolecular and Cellular Biology
Volume16
Issue number10
Publication statusPublished - 1996

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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