A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype.
AUTOR(ES)
Collesi, C
RESUMO
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 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 (delta-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 beta-chain extracellular domain. The deleted transcript originates 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 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 delta-Ron isoform. Inhibition of thiol-mediated intermolecular disulfide bonding prevented delta-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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=231551Documentos Relacionados
- Characterization of an Acholeplasma laidlawii variant with a REP- phenotype.
- Constitutive activation of the RON gene promotes invasive growth but not transformation.
- Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype.
- Dysregulation of Met receptor tyrosine kinase activity in invasive tumors
- RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP.