A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations

Toshihide Iwashita, Hideki Murakami, Kei Kurokawa, Kumi Kawai, Akira Miyauchi, Hitoyasu Futami, Shanlou Qiao, Masatoshi Ichihara, Masahide Takahashi

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

Multiple endocrine neoplasia (MEN) type 2B mutations have been reported at methionine 918 or alanine 883 in the tyrosine kinase domain of the RET proto-oncogene. Recently, a new combination of two germline missense mutations at valine 804 and tyrosine 806 was identified in a patient with MEN 2B-like clinical phenotypes including medullary thyroid carcinoma, mucosal neuroma, and marfanoid habitus. In this case, valine 804 and tyrosine 806 were replaced with methionine and cysteine, respectively. In the present study, biological activities of RET with these new mutations were compared with those with known MEN 2A or MEN 2B mutations. The transforming activity of RET with the V804M/Y806C mutation was about 8- to 13-fold higher than that of RET with a single V804M or Y806C mutation. Like RET with the M918T or A883F MEN 2B mutation, the transforming activity of RET with the V804M/Y806C mutation was not affected by substitution of phenylalanine for tyrosine 905 that abolished the activity of RET with the MEN 2A mutation. On the other hand, substitution of phenylalanine for tyrosines 864 and 952 drastically diminished the activity of RET with the V804M/Y806C, M918T or A883F mutation, suggesting that these three mutant proteins have similar biological properties. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)804-808
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume268
Issue number3
DOIs
Publication statusPublished - 24-02-2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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