Bargmann C I, Weinberg R A
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 01242.
EMBO J. 1988 Jul;7(7):2043-52. doi: 10.1002/j.1460-2075.1988.tb03044.x.
The rat neu gene, which encodes a receptor-like protein homologous to the epidermal growth factor receptor, is frequently activated by a point mutation altering a valine residue to a glutamic acid residue in its predicted transmembrane domain. Additional point mutations have been constructed in a normal neu cDNA at and around amino acid position 664, the site of the naturally arising mutation. A mutation which causes a substitution of a glutamine residue for the normal valine at residue 664 leads to full oncogenic activation of the neu gene, but five other substitutions do not. Substituted glutamic acid residues at amino acid positions 663 or 665 do not activate the neu gene. Thus only a few specific residues at amino acid residue 664 can activate the oncogenic potential of the neu gene. Deletion of sequences of the transforming neu gene demonstrates that no more than 420 amino acids of the 1260 encoded by the gene are required for full transforming function. Mutagenesis of the transforming clone demonstrates a correlation between transforming activity and tyrosine kinase activity. These data indicate that the activating point mutation induces transformation through (or together with) the activities of the tyrosine kinase.
大鼠neu基因编码一种与表皮生长因子受体同源的受体样蛋白，该基因经常通过一个点突变而被激活，此突变在其预测的跨膜结构域中将一个缬氨酸残基改变为谷氨酸残基。在正常的neu cDNA中，已在天然发生突变的位点（氨基酸位置664及其周围）构建了额外的点突变。在第664位残基处，一个导致正常缬氨酸被谷氨酰胺残基取代的突变会导致neu基因完全致癌激活，但其他五个取代则不会。在氨基酸位置663或665处的取代谷氨酸残基不会激活neu基因。因此，只有在氨基酸残基664处的少数特定残基才能激活neu基因的致癌潜能。对转化性neu基因序列的缺失表明，该基因编码的1260个氨基酸中，不超过420个氨基酸对于完全转化功能是必需的。对转化性克隆的诱变表明转化活性与酪氨酸激酶活性之间存在相关性。这些数据表明，激活点突变通过酪氨酸激酶的活性（或与之一起）诱导转化。
