An activating mutation in the ATP binding site of the ABL kinase domain
An activating mutation in the ATP binding site of the ABL kinase domain
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DOI：
10.1074/jbc.271.32.19585
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发表时间：
1996-08-09
影响因子：
4.8
通讯作者：
Wiedemann, LM
中科院分区：
文献类型：
--
作者：
Allen, PB;Wiedemann, LM
一些结构改变已被证明激活白血病的潜力ABL癌基因，但有很少的了解被颠覆的这种变化的调节机制。我们已经使用定向诱变来检查cABL中的潜在调节基序，其可以直接影响ABL酪氨酸激酶活性。ABL激酶结构域的ATP结合折叠内的酪氨酸至苯丙氨酸取代足以激活cABL酶活性，并且当在BA/F3细胞系中表达时，突变蛋白将减轻生长因子依赖性。这种生长促进依赖于蛋白质氨基末端的结构，并且ABL突变将与BCR/ABL融合蛋白中的某些BCR序列协作以解除ABL激酶活性的调节。
A number of structural alterations have been shown to activate the leukemogenic potential of the ABL oncogene, but there is little understanding of the regulatory mechanisms that are subverted by such changes. We have used directed mutagenesis to examine a potential regulatory motif in cABL, which could directly influence ABL tyrosine kinase activity. A tyrosine to phenylalanine substitution within the ATP binding fold of the ABL kinase domain is sufficient to activate cABL enzymatic activity, and the mutant protein will alleviate growth factor dependence when expressed in the BA/F3 cell line. This growth promotion is dependent upon the structure of the amino terminus of the protein, and the ABL mutation will cooperate with certain BCR sequences in BCR/ABL fusion proteins to deregulate ABL kinase activity.