RET activation by germline MEN2A and MEN2B mutations

Maria Grazia Borrello, Darrin P. Smith, Barbara Pasini, Italia Bongarzone, Angela Greco, Maria J. Lorenzo, Elena Arighi, Claudia Miranda, Charis Eng, Luisella Alberti, Renata Bocciardi, Piera Mondellini, Lucio Scopsi, Giovanni Romeo, Bruce A J Ponder, Marco A. Pierotti

Research output: Contribution to journalArticlepeer-review


The RET proto-oncogene encodes a receptor tyrosine kinase (TK). It has been shown that distinct germline mutations in the RET proto-oncogene are associated with the dominantly inherited cancer syndromes multiple endocrine neoplasia type 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC) as well as Hirschsprung disease (HSCR), a congenital disorder characterised by absent enteric innervation. In this study, we have transfected NIH3T3 and PC12 phaeochromocytoma cells with MEN2A (Cys634→Arg) and MEN2B (Met918→Thr) RET constructs. Both caused transformation of the NIH3T3 cells and differentiation of PC12 cells. The Ret (MEN2A) and Ret (MEN2B) proteins were constitutively phosphorylated on tyrosine, and their in vitro kinase activity was significantly higher than that of the wild type protein. The MTC cell line TT carries a Cys634→Trp MEN2A mutation, and we have shown by immunoelectronmicroscopy that Ret is clustered on the cell surface in a manner reminiscent of ligand-induced aggregation of cell surface receptors. RET is activated, as RET/PTC oncogene, by somatic rearrangements which link the TK domain to a constitutive dimerization interface in papillary thyroid carcinomas. We have compared the biological and biochemical activity of the TK domains of the wild type and MEN 2B Ret in the context of the RET/PTC. The results show that the MEN2B mutation significantly increases the TK domain enzymatic activity suggesting that dimerization may be still necessary for MEN 2B Ret to express its full activity.

Original languageEnglish
Pages (from-to)2419-2427
Number of pages9
Issue number11
Publication statusPublished - Dec 7 1995


  • Inherited cancer syndrome
  • Multiple endocrine neoplasia type 2
  • Oncogene
  • Receptor tyrosine kinase
  • RET

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics


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