RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant

Malignant gliomas are incurable because of their diffuse infiltration of the surrounding brain. The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly expressed in several epithelial cancer types and mediates tumorigenic, pro-invasive as well as metastatic effects. Analyzing RON expression in human gliomas, we found that different splice variants with known oncogenic activity are expressed in glioblastomas (GBM). In addition, the RON ligand macrophage-stimulating protein (MSP) is secreted by cultured GBM cells. MSP showed no mitogenic effect on GBM cells but displayed significant chemotactic activity for several GBM cell lines. We identified a novel splice variant, RON Delta 90, which is generated by a transcript missing exon 6. As a result of a frameshift, translation is terminated in exon 7, resulting in a truncated soluble protein. RON Delta 90 transcripts are expressed in normal human brain as well as in low grade astrocytomas but only in approximately 50% of highly malignant astrocytomas. In addition, RON Delta 90 is detectable in supernatants of GBM cell lines. We cloned the RON Delta 90 cDNA, and purified the recombinant protein from transfected cells. RON Delta 90 inhibited MSP-induced phosphorylation of cellular RON and also attenuated basal activation levels. In addition, RON Delta 90 inhibited MSP-induced glioma cell migration as well as random motility. To conclude, RON Delta 90 is a novel soluble receptor variant with antagonistic activity that may act as a physiological modulator of RON signaling. The expression of several oncogenic RON splice variants in malignant gliomas suggests that these could represent candidate targets for treatment with agents inhibiting RON activity.