Multiple variants of the RON receptor tyrosine kinase: Biochemical properties, tumorigenic activities, and potential drug targets

作者：Lu Yi; Yao Hang Ping; Wang Ming Hal

来源：Cancer Letters, 2007, 257(2): 157-164.

DOI：10.1016/j.canlet.2007.08.007

• receptor tyrosine kinase
• alternative splicing
• oncogenic signal
• invasive growth
• therapeutical target

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 RON Delta 170, Delta 165, Delta 160, Delta 155, Delta 110, and Delta 55 with various deletions or truncations in the extracellular or intracellular regions have been identified. The extracellular sequences contain functional structures such as sema domain, PS I motif, and I PT units. The deletion or truncation results in constitutive phosphorylation and increased kinase activities. Oncogenic RON Delta 160, generated by exclusion of the first IPT unit, is a typical example. In contrast, the deletion adjacent to the conserved MET1254 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.

• 出版日期2007-11-18
• 单位浙江大学