Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations

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

研究成果: Article

26 引用 (Scopus)

抄録

Biological and biochemical effects of multiple endocrine neoplasia type 2A (MEN-2A), type 2B (MEN-2B) and familial medullary thyroid carcinoma (FMTC) mutations on Ret function were investigated by transfection of NIH 3T3 cells. All mutations examined conferred transforming activity on Ret at variable levels. Cysteine mutations detected in MEN-2A and FMTC induced disulphide- linked homodimers of Pet on the cell surface, leading to activation of its intrinsic tyrosine kinase. Of these cysteine-mutated proteins, Ret with a codon 634 mutation had the highest transforming activity. The activity of Ret with a codon 609, 611, 618 or 620 mutation was approximately three- to five- fold lower than that of Ret with a codon 634 mutation. The first four mutations impaired the Ret cell surface expression or its correct maturation, resulting in the low transforming activity. On the other hand, the MEN-2B mutation appeared to activate Ret by an intramolecular mechanism without dimerization. In addition, we investigated the role of tyrosines present in the intracellular domain for the transforming activity of the mutant Ret proteins. As a result, we found that tyrosine 905 is essential for the transforming activity of the MEN-2A-Ret mutant protein whereas tyrosines 864 and 952 are critical for that of the MEN-2B-Ret mutant protein. Moreover, it turned out that tyrosine 1062 regulates the activity of both MEN-2A-Ret and MEN-2B-Ret and represents a binding site for the Shc adaptor protein.

元の言語English
ページ(範囲)509-513
ページ数5
ジャーナルJournal of Internal Medicine
243
発行部数6
出版物ステータスPublished - 16-07-1998

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Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 2a
Mutation
Multiple Endocrine Neoplasia Type 2b
Tyrosine
Mutant Proteins
Codon
Cysteine
Shc Signaling Adaptor Proteins
NIH 3T3 Cells
Pets
Dimerization
Disulfides
Protein-Tyrosine Kinases
Transfection
Binding Sites

All Science Journal Classification (ASJC) codes

  • Internal Medicine

これを引用

Takahashi, M. ; Asai, N. ; Iwashita, T. ; Murakami, H. ; Ito, S. / Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations. :: Journal of Internal Medicine. 1998 ; 巻 243, 番号 6. pp. 509-513.
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abstract = "Biological and biochemical effects of multiple endocrine neoplasia type 2A (MEN-2A), type 2B (MEN-2B) and familial medullary thyroid carcinoma (FMTC) mutations on Ret function were investigated by transfection of NIH 3T3 cells. All mutations examined conferred transforming activity on Ret at variable levels. Cysteine mutations detected in MEN-2A and FMTC induced disulphide- linked homodimers of Pet on the cell surface, leading to activation of its intrinsic tyrosine kinase. Of these cysteine-mutated proteins, Ret with a codon 634 mutation had the highest transforming activity. The activity of Ret with a codon 609, 611, 618 or 620 mutation was approximately three- to five- fold lower than that of Ret with a codon 634 mutation. The first four mutations impaired the Ret cell surface expression or its correct maturation, resulting in the low transforming activity. On the other hand, the MEN-2B mutation appeared to activate Ret by an intramolecular mechanism without dimerization. In addition, we investigated the role of tyrosines present in the intracellular domain for the transforming activity of the mutant Ret proteins. As a result, we found that tyrosine 905 is essential for the transforming activity of the MEN-2A-Ret mutant protein whereas tyrosines 864 and 952 are critical for that of the MEN-2B-Ret mutant protein. Moreover, it turned out that tyrosine 1062 regulates the activity of both MEN-2A-Ret and MEN-2B-Ret and represents a binding site for the Shc adaptor protein.",
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Takahashi, M, Asai, N, Iwashita, T, Murakami, H & Ito, S 1998, 'Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations', Journal of Internal Medicine, 巻. 243, 番号 6, pp. 509-513.

Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations. / Takahashi, M.; Asai, N.; Iwashita, T.; Murakami, H.; Ito, S.

:: Journal of Internal Medicine, 巻 243, 番号 6, 16.07.1998, p. 509-513.

研究成果: Article

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T1 - Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations

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AU - Asai, N.

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AU - Murakami, H.

AU - Ito, S.

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AB - Biological and biochemical effects of multiple endocrine neoplasia type 2A (MEN-2A), type 2B (MEN-2B) and familial medullary thyroid carcinoma (FMTC) mutations on Ret function were investigated by transfection of NIH 3T3 cells. All mutations examined conferred transforming activity on Ret at variable levels. Cysteine mutations detected in MEN-2A and FMTC induced disulphide- linked homodimers of Pet on the cell surface, leading to activation of its intrinsic tyrosine kinase. Of these cysteine-mutated proteins, Ret with a codon 634 mutation had the highest transforming activity. The activity of Ret with a codon 609, 611, 618 or 620 mutation was approximately three- to five- fold lower than that of Ret with a codon 634 mutation. The first four mutations impaired the Ret cell surface expression or its correct maturation, resulting in the low transforming activity. On the other hand, the MEN-2B mutation appeared to activate Ret by an intramolecular mechanism without dimerization. In addition, we investigated the role of tyrosines present in the intracellular domain for the transforming activity of the mutant Ret proteins. As a result, we found that tyrosine 905 is essential for the transforming activity of the MEN-2A-Ret mutant protein whereas tyrosines 864 and 952 are critical for that of the MEN-2B-Ret mutant protein. Moreover, it turned out that tyrosine 1062 regulates the activity of both MEN-2A-Ret and MEN-2B-Ret and represents a binding site for the Shc adaptor protein.

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