TY - JOUR
T1 - A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations
AU - Iwashita, Toshihide
AU - Murakami, Hideki
AU - Kurokawa, Kei
AU - Kawai, Kumi
AU - Miyauchi, Akira
AU - Futami, Hitoyasu
AU - Qiao, Shanlou
AU - Ichihara, Masatoshi
AU - Takahashi, Masahide
N1 - Funding Information:
We are grateful to K. Imaizumi, J. Aoki, K. Uchiyama, and M. Kozuka for their technical assistance. This work was supported in part by grants-in-aid for COE research, Scientific research and Cancer research from the Ministry of Education, Science, Sports and Culture of Japan and by a grant from the Mitsubishi Foundation.
PY - 2000/2/24
Y1 - 2000/2/24
N2 - 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.
AB - 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.
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U2 - 10.1006/bbrc.2000.2227
DO - 10.1006/bbrc.2000.2227
M3 - Article
C2 - 10679286
AN - SCOPUS:0034708059
SN - 0006-291X
VL - 268
SP - 804
EP - 808
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -