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

Massimo Mattia Santoro, Lorenza Penengo, Marta Minetto, Sara Orecchia, Michele Cilli, Giovanni Gaudino

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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 Pet 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-phosphorylated 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.

Original languageEnglish
Pages (from-to)741-749
Number of pages9
JournalOncogene
Volume17
Issue number6
Publication statusPublished - Aug 13 1998

Fingerprint

Point Mutation
Protein-Tyrosine Kinases
Phosphotransferases
Multiple Endocrine Neoplasia Type 2b
Fibroblasts
Mastocytosis
Neoplasms
Mutation
MAP Kinase Signaling System
Amino Acid Substitution
Substrate Specificity
Nude Mice
Tyrosine
Carcinogenesis
Neoplasm Metastasis
Proteins

Keywords

  • Metastasis
  • Ron
  • Signal transduction
  • Tumorigenesis
  • Tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Santoro, M. M., Penengo, L., Minetto, M., Orecchia, S., Cilli, M., & Gaudino, G. (1998). Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor. Oncogene, 17(6), 741-749.

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor. / Santoro, Massimo Mattia; Penengo, Lorenza; Minetto, Marta; Orecchia, Sara; Cilli, Michele; Gaudino, Giovanni.

In: Oncogene, Vol. 17, No. 6, 13.08.1998, p. 741-749.

Research output: Contribution to journalArticle

Santoro, MM, Penengo, L, Minetto, M, Orecchia, S, Cilli, M & Gaudino, G 1998, 'Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor', Oncogene, vol. 17, no. 6, pp. 741-749.
Santoro MM, Penengo L, Minetto M, Orecchia S, Cilli M, Gaudino G. Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor. Oncogene. 1998 Aug 13;17(6):741-749.
Santoro, Massimo Mattia ; Penengo, Lorenza ; Minetto, Marta ; Orecchia, Sara ; Cilli, Michele ; Gaudino, Giovanni. / Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor. In: Oncogene. 1998 ; Vol. 17, No. 6. pp. 741-749.
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