Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets.
Aberrant expression of the RON (Recepteur d'Origine Nantais) receptor tyrosine kinase, accompanied by generation of multiple splicing or truncated variants, contributes to pathogenesis of epithelial cancers. Currently, six variants including RONDelta170, Delta165, Delta160, Delta155, Delta110, and Delta55 with various deletions or truncations in the extracellular or intracellular regions have been identified. The extracellular sequences contain functional structures such as sema domain, PSI motif, and IPT units. The deletion or truncation results in constitutive phosphorylation and increased kinase activities. Oncogenic RONDelta160, generated by exclusion of the first IPT unit, is a typical example. In contrast, the deletion adjacent to the conserved MET(1254) in the kinase domain converts RON into a dominant negative agent. Among three mechanisms underlying isoform production, the switch from constitutive to alternative pre-mRNA splicing is the major event in producing RON variants in cancer cells. Most of the RON variants have the ability to activate multiple signaling cascades with a different substrate specificity and phosphorylation profile. They regulate cell migration, invasion, and proliferation, which contribute to the invasive phenotype and promote the malignant progression. Thus, determining the pathogenesis of RON variants is critical in understanding the mechanisms underlying cancer initiation and progression. Targeting oncogenic signals elicited by RON or its variants by special antibody or small interfering RNA could provide a novel strategy for the treatment of malignant epithelial cancers.
Lu
Yi
Y
Laboratory of Cancer Biology and Therapeutics, Institute of Infectious Diseases at First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, People's Republic of China.
Yao
Hang-Ping
HP
Wang
Ming-Hai
MH
D017398:Alternative Splicing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D007527:Isoenzymes; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases