Mechanism of Ret activation by a mutation at aspartic acid 631 identified in sporadic pheochromocytoma.
Mutations at aspartic acid 631 in Ret were reported in sporadic pheochromocytoma and medullary thyroid carcinoma. We replaced this aspartic acid with four other amino acids including tyrosine, glycine, asparagine, and alanine and investigated the transforming activity of these mutant cDNAs. Among them, RET cDNA with a mutation of aspartic acid to tyrosine (D631Y) that was reported in sporadic pheochromocytoma showed high transforming activity. The D631Y mutation activated Ret by inducing its disulfide-linked dimerization in the transfectant as observed for multiple endocrine neoplasia (MEN) 2A mutations at cysteine 609, 611, 618, 620, 630, or 634. Further mutation analysis suggested that cysteine 630 or 634 could be involved in the disulfide-linked Ret dimerization induced by the D631Y mutation.
Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Nagoya, Showa-ku, 466-8550, Japan.
N
N
Asai
T
T
Iwashita
H
H
Murakami
H
H
Takanari
K
K
Ohmori
M
M
Ichihara
M
M
Takahashi
D016475:3T3 Cells; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D029721:Drosophila Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D051379:Mice; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014162:Transfection / Q000235:genetics; D014170:Transformation, Genetic
D004273:DNA, Neoplasm; D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D001224:Aspartic Acid; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse