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 th...

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Published in:Biochemical and biophysical research communications 1999-02, Vol.255 (3), p.587-590
Main Authors: Asai, Naoya, Iwashita, Toshihide, Murakami, Hideki, Takanari, Hiroki, Ohmori, Kenji, Ichihara, Masatoshi, Takahashi, Masahide
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Aspartic Acid - genetics
DNA Mutational Analysis
DNA, Neoplasm - genetics
Drosophila Proteins
Gene Expression Regulation, Neoplastic - genetics
Mice
Multiple Endocrine Neoplasia - genetics
Mutation - genetics
Pheochromocytoma - genetics
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases - genetics
Transfection - genetics
Transformation, Genetic
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Summary: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,RETcDNA 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.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1999.0237