Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma

Toshihide Iwashita, Masashi Kato, Hideki Murakami, Naoya Asai, Yoshihiro Ishiguro, Shinji Ito, Yosuke Iwata, Kumi Kawai, Masami Asai, Kei Kurokawa, Hiroshi Kajita, Masahide Takahashi

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Abstract

Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with endocrine neoplasia (MEN) 2B, familial (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768→aspartic acid (E768D), valine 804→leucine (V804L), alanine 883→phenylalanine (A883F), serine 891→alanine (S891A), methionine 918→threonine (M918T), alanine 919→proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.

Original languageEnglish
Pages (from-to)3919-3922
Number of pages4
JournalOncogene
Volume18
Issue number26
DOIs
Publication statusPublished - 01-07-1999

Fingerprint

Multiple Endocrine Neoplasia Type 2b
Alanine
Phosphotransferases
Valine
Mutation
Methionine
Serine
Protein Isoforms
Complementary DNA
Proto-Oncogenes
Phenylalanine
Tyrosine
Glutamic Acid
Familial medullary thyroid carcinoma
Phenotype
Acids
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Iwashita, Toshihide ; Kato, Masashi ; Murakami, Hideki ; Asai, Naoya ; Ishiguro, Yoshihiro ; Ito, Shinji ; Iwata, Yosuke ; Kawai, Kumi ; Asai, Masami ; Kurokawa, Kei ; Kajita, Hiroshi ; Takahashi, Masahide. / Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. In: Oncogene. 1999 ; Vol. 18, No. 26. pp. 3919-3922.
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title = "Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma",
abstract = "Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with endocrine neoplasia (MEN) 2B, familial (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768→aspartic acid (E768D), valine 804→leucine (V804L), alanine 883→phenylalanine (A883F), serine 891→alanine (S891A), methionine 918→threonine (M918T), alanine 919→proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.",
author = "Toshihide Iwashita and Masashi Kato and Hideki Murakami and Naoya Asai and Yoshihiro Ishiguro and Shinji Ito and Yosuke Iwata and Kumi Kawai and Masami Asai and Kei Kurokawa and Hiroshi Kajita and Masahide Takahashi",
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Iwashita, T, Kato, M, Murakami, H, Asai, N, Ishiguro, Y, Ito, S, Iwata, Y, Kawai, K, Asai, M, Kurokawa, K, Kajita, H & Takahashi, M 1999, 'Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma', Oncogene, vol. 18, no. 26, pp. 3919-3922. https://doi.org/10.1038/sj.onc.1202742

Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. / Iwashita, Toshihide; Kato, Masashi; Murakami, Hideki; Asai, Naoya; Ishiguro, Yoshihiro; Ito, Shinji; Iwata, Yosuke; Kawai, Kumi; Asai, Masami; Kurokawa, Kei; Kajita, Hiroshi; Takahashi, Masahide.

In: Oncogene, Vol. 18, No. 26, 01.07.1999, p. 3919-3922.

Research output: Contribution to journalArticle

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T1 - Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma

AU - Iwashita, Toshihide

AU - Kato, Masashi

AU - Murakami, Hideki

AU - Asai, Naoya

AU - Ishiguro, Yoshihiro

AU - Ito, Shinji

AU - Iwata, Yosuke

AU - Kawai, Kumi

AU - Asai, Masami

AU - Kurokawa, Kei

AU - Kajita, Hiroshi

AU - Takahashi, Masahide

PY - 1999/7/1

Y1 - 1999/7/1

N2 - Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with endocrine neoplasia (MEN) 2B, familial (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768→aspartic acid (E768D), valine 804→leucine (V804L), alanine 883→phenylalanine (A883F), serine 891→alanine (S891A), methionine 918→threonine (M918T), alanine 919→proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.

AB - Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with endocrine neoplasia (MEN) 2B, familial (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768→aspartic acid (E768D), valine 804→leucine (V804L), alanine 883→phenylalanine (A883F), serine 891→alanine (S891A), methionine 918→threonine (M918T), alanine 919→proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.

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