RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant.
J Neurochem
; 109(4): 969-80, 2009 May.
Article
em En
| MEDLINE
| ID: mdl-19519771
ABSTRACT
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, RONDelta90, 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. RONDelta90 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, RONDelta90 is detectable in supernatants of GBM cell lines. We cloned the RONDelta90 cDNA, and purified the recombinant protein from transfected cells. RONDelta90 inhibited MSP-induced phosphorylation of cellular RON and also attenuated basal activation levels. In addition, RONDelta90 inhibited MSP-induced glioma cell migration as well as random motility. To conclude, RONDelta90 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Encefálicas
/
Receptores Proteína Tirosina Quinases
/
Glioma
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Alemanha