Mechanisms of development of multiple endocrine neoplasia type 2 and Hirschsprung's disease by ret mutations.

M. Takahashi, N. Asai, T. Iwashita, H. Murakami, S. Ito

Research output: Contribution to journalReview articlepeer-review

14 Citations (Scopus)


The ret proto-oncogene encodes a receptor tyrosine kinase whose ligands belong to the glial cell line-derived neurotrophic factor (GDNF) protein family. Its germline mutations are responsible for the development of multiple endocrine neoplasia (MEN) types 2A and 2B and Hirschsprung's disease (HSCR). MEN2A and MEN2B mutations result in the constitutive activation of Ret by different molecular mechanisms. MEN2A mutations involve cysteine residues present in the Ret extracellular domain and induce disulfide-linked Ret dimerization on the cell surface. MEN2B mutations were identified in methionine 918 in the tyrosine kinase domain and activate Ret without dimerization, probably due to a conformational change of its catalytic core region. In contrast to MEN2 mutations, HSCR mutations represent loss of function mutations. We found that most of HSCR mutations detected in the extracellular domain impair the Ret cell surface expression. More interestingly, ret mutations in cysteines 618 and 620 were reported in several families who developed both MEN2A and HSCR. It was suggested that these mutations might have two biological effects on Ret function, leading to the development of different clinical phenotypes in the same patients.

Original languageEnglish
Pages (from-to)229-236
Number of pages8
JournalRecent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer
Publication statusPublished - 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


Dive into the research topics of 'Mechanisms of development of multiple endocrine neoplasia type 2 and Hirschsprung's disease by ret mutations.'. Together they form a unique fingerprint.

Cite this