A novel activating mutation in the RET tyrosine kinase domain mediates neoplastic transformation

Aaron Cranston, Cristiana Carniti, Sam Martin, Piera Mondellini, Yvette Hooks, Jean Leyland, Shirley Hodgson, Sue Clarke, Marco Pierotti, Bruce A J Ponder, Italia Bongarzone

Research output: Contribution to journalArticlepeer-review


We report the finding of a novel missense mutation at codon 833 in the tyrosine kinase of the RET proto-oncogene in a patient with a carcinoma of the thyroid. In vitro experiments demonstrate that the R833C mutation induces transformed foci only when present in the long 3′ splice isoform and, in keeping with a model in which the receptor has to dimerize to be completely activated, glial cell line-derived neurotrophic factor stimulation leads the RETR833C receptor to a higher level of activation. Tyrosine kinase assays show that the RETR833C long isoform has weak intrinsic kinase activity and phosphorylation of an exogenous substrate is not elevated even in the presence of glial cell line-derived neurotrophic factor. Furthermore, the R833C mutation is capable of sustaining the transformed phenotype in vivo but does not confer upon the transformed cells the ability to degrade the basement membrane in a manner analogous to metastasis. Our functional characterization of the R833C substitution suggests that, like the V804M and S891A mutations, this tyrosine kinase mutation confers a weak activating potential upon RET. This is the first report demonstrating that the introduction of an intracellular cysteine can activate RET. However, this does not occur via dimerization in a manner analogous to the extracellular cysteine mutants.

Original languageEnglish
Pages (from-to)1633-1643
Number of pages11
JournalMolecular Endocrinology
Issue number7
Publication statusPublished - 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism


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