Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor
| Autor: | Lorenza Penengo, Marta Minetto, Sara Orecchia, Giovanni Gaudino, Michele Cilli, Massimo Santoro |
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| Přispěvatelé: | University of Zurich, Gaudino, G |
| Rok vydání: | 1998 |
| Předmět: |
Cancer Research
Lung Neoplasms Mice Nude 610 Medicine & health Receptors Cell Surface Tropomyosin receptor kinase C Receptor tyrosine kinase Mice 1311 Genetics Proto-Oncogene Proteins 1312 Molecular Biology Genetics Animals Drosophila Proteins Humans Point Mutation 1306 Cancer Research Neoplasm Metastasis Phosphorylation Molecular Biology Mitogen-Activated Protein Kinase 1 biology 10061 Institute of Molecular Cancer Research Proto-Oncogene Proteins c-ret JNK Mitogen-Activated Protein Kinases MST1R Receptor Protein-Tyrosine Kinases 3T3 Cells Oncogenes Protein-Tyrosine Kinases Proto-Oncogene Proteins c-kit Cell Transformation Neoplastic Phenotype COS Cells Calcium-Calmodulin-Dependent Protein Kinases ROR1 biology.protein Cancer research 570 Life sciences Sarcoma Experimental Mitogen-Activated Protein Kinases Protein Kinases Tyrosine kinase HeLa Cells Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1201994 |
| Popis: | Ron (the receptor for Macrophage Stimulating Protein) has never been implicated before in human malignancies or in cell transformation. In this report we show that Ron can acquire oncogenic potential by means of two amino acid substitutions-D1232V and M1254T-affecting highly conserved residues in the tyrosine kinase domain. The same mutations in Kit and Ret have been found associated with two human malignancies, mastocytosis and Multiple Endocrine Neoplasia type 2B (MEN2B), respectively. Both mutations caused Ron-mediated transformation of 3T3 fibroblasts and tumour formation in nude mice. Moreover, cells transformed by the oncogenic Ron mutants displayed high metastatic potential. The Ron mutant receptors were constitutively active and the catalytic efficiency of the mutated kinase was higher than that of wild-type Ron. Oncogenic Ron mutants enhanced activation of the Ras/MAPK cascade with respect to wild type Ron, without affecting the JNK/SAPK pathway. Expression of Ron mutants in 3T3 fibroblasts led to different patterns of tyrosine-phos-phorylated proteins. These data show that point mutations altering catalytic properties and possibly substrate specificity of the Ron kinase may force cells toward tumorigenesis and metastasis. |
| Databáze: | OpenAIRE |
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