Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations

Mireille Rossel, Andrea Pasini, Sophie Chappuis, Olivier Geneste, Laurence Fournier, Isabelle Schuffenecker, Masahide Takahashi, Leo A. Van Grunsven, José Luis Urdiales, Brian B. Rudkin, Gilbert M. Lenoir, Marc Billaud

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)

Abstract

Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634 → Arg) and the unique MEN 2B mutation (Met918 → Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.

Original languageEnglish
Pages (from-to)265-275
Number of pages11
JournalOncogene
Volume14
Issue number3
DOIs
Publication statusPublished - 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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