A mutation in the RET proto-oncogene in Hirschsprung's disease affects the tyrosine kinase activity associated with multiple endocrine neoplasia type 2A and 2B.
A mutation in the RET proto-oncogene in Hirschsprung's disease affects the tyrosine kinase activity associated with multiple endocrine neoplasia type 2A and 2B.
复制标题
先天性巨结肠中 RET 原癌基因的突变会影响与 2A 型和 2B 型多发性内分泌肿瘤相关的酪氨酸激酶活性。
DOI：
10.1042/bj3140397
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
V. Colantuoni
中科院分区：
文献类型：
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作者：
M. Cosma;L. Panariello;L. Quadro;N. Dathan;O. Fattoruso;V. Colantuoni
我们证明，先天性巨结肠（HSCR）突变的RET原癌基因的酪氨酸激酶结构域废除顺式酪氨酸磷酸化与激活突变的多发性内分泌腺瘤2A型（MEN2A）在瞬时转染的Cos细胞。然而，双突变体RET2AHS保留了形成稳定二聚体的能力，从而使二聚化与磷酸化潜力分离。以不同比例携带质粒RET2A和RET2AHS的单突变体和双突变体的共转染实验显著降低了RET2A蛋白的磷酸化水平，表明HSCR突变的显性负效应。此外，与多发性内分泌瘤2B型（MEN2B）等位基因相关的磷酸化在相同条件下共转染质粒的单突变体和双突变体的实验中受到影响。最后，MEN2A和MEN2B肿瘤的酶活性分析证实了在Cos细胞中观察到的酪氨酸磷酸化的相对水平，表明这种情况在体内可能是RET转化潜力的原因。
We demonstrate that a Hirschsprung (HSCR) mutation in the tyrosine kinase domain of the RET proto-oncogene abolishes in cis the tyrosine-phosphorylation associated with the activating mutation in multiple endocrine neoplasia type 2A (MEN2A) in transiently transfected Cos cells. Yet the double mutant RET2AHS retains the ability to form stable dimers, thus dissociating the dimerization from the phosphorylation potential. Co-transfection experiments with single and double mutants carrying plasmids RET2A and RET2AHS in different ratios drastically reduced the phosphorylation levels of the RET2A protein, suggesting a dominant-negative effect of the HSCR mutation. Also, the phosphorylation associated with the multiple endocrine neoplasia type 2B (MEN2B) allele was affected in experiments with single and double mutants carrying plasmids co-transfected under the same conditions. Finally, analysis of the enzymic activity of MEN2A and MEN2B tumours confirmed the relative levels of tyrosine phosphorylation observed in Cos cells, indicating that this condition, in vivo, may account for the RET transforming potential.