Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

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 th...

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Bibliographic Details
Published in:Oncogene Vol. 17; no. 6; pp. 741 - 749
Main Authors: Santoro, Massimo Mattia, Penengo, Lorenza, Minetto, Marta, Orecchia, Sara, Cilli, Michele, Gaudino, Giovanni
Format: Journal Article
Language:English
Published: Basingstoke Nature Publishing 13.08.1998
Nature Publishing Group
Subjects:
3T3 Cells
Amino acids
Animals
Biological and medical sciences
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Cell Transformation, Neoplastic - genetics
COS Cells
Drosophila Proteins
Fibroblasts
Fundamental and applied biological sciences. Psychology
Genetic transformation
HeLa Cells
Humans
JNK Mitogen-Activated Protein Kinases
Kinases
Lung Neoplasms - pathology
Macrophages
MAP kinase
Mastocytosis
Metastases
Metastasis
Mice
Mice, Nude
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Molecular and cellular biology
Multiple endocrine neoplasia
Mutants
Mutation
Neoplasm Metastasis
Neuroendocrine tumors
Oncogenes
Phenotype
Phosphorylation
Point Mutation
Protein Kinases - metabolism
Protein-tyrosine kinase
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-kit - genetics
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Ret protein
Sarcoma, Experimental - pathology
Signal Transduction
Substrate specificity
Tumorigenesis
Tumors
Human
Macrophage activating factor
Gene
Enzyme
Transferases
Point mutation
Tumor progression
Metastasis
Cell transformation
Carcinogenesis
Protein-tyrosine kinase
Biological receptor
ISSN:0950-9232, 1476-5594
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Summary: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.
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ISSN:0950-9232
1476-5594
DOI:10.1038/sj.onc.1201994