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 language | English |
|---|---|
| Pages (from-to) | 3919-3922 |
| Number of pages | 4 |
| Journal | Oncogene |
| Volume | 18 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - 01-07-1999 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Cancer Research
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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 journal › Article
TY - JOUR
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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U2 - 10.1038/sj.onc.1202742
DO - 10.1038/sj.onc.1202742
M3 - Article
C2 - 10445857
AN - SCOPUS:0033166442
VL - 18
SP - 3919
EP - 3922
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 26
ER -