Phosphorylation of tyrosine 393 in the kinase domain of Bcr-Abl influences the sensitivity towards imatinib in vivo
Phosphorylation of tyrosine 393 in the kinase domain of Bcr-Abl influences the sensitivity towards imatinib in vivo
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Bcr-Abl 激酶结构域中酪氨酸 393 的磷酸化影响体内对伊马替尼的敏感性
作者：
C. Miething;C. Mugler;R. Grundler;J. Hoepfl;Ren;C. Peschel;J. Duyster
通过t(9;22)（q34;q11）相互易位产生的Bcr-Abl融合蛋白是慢性髓性白血病和急性淋巴细胞白血病亚群的致病因子。甲磺酸伊马替尼是一种特异性的Bcr-Abl激酶抑制剂，在临床研究中显示出良好的效果。Bcr-Abl癌基因和酪氨酸激酶抑制剂伊马替尼之间的结构关系最近通过一种优雅的晶体结构分析得到阐明，强调了Bcr-Abl中去磷酸化酪氨酸393 （Tyr393）对抑制剂进入激酶结构域的重要性。通过将酪氨酸突变为苯丙氨酸，从而模拟组成性去磷酸化状态，我们现在表明，由这种突变体转化的Ba/F3细胞在体内对伊马替尼的敏感性增加。这种效应不是由于Bcr-Abl Y393F的激酶活性受损，因为合成底物以类似的动力学被磷酸化。用磷酸酶抑制剂处理转染Bcr-Abl野生型的Ba/F3细胞，伊马替尼的作用减弱，但不影响转染Bcr-AblY393F的Ba/F3细胞的生长。这些结果支持了晶体结构的发现，表明Tyr393确实在体内对Bcr-Abl对伊马替尼的敏感性中起重要作用。这些数据暗示Tyr393磷酸化调控是伊马替尼耐药的潜在机制。
The Bcr-Abl fusion protein arising through the t(9;22)(q34;q11) reciprocal translocation is the causative agent in chronic myeloid leukemia and a subset of acute lymphocytic leukemia. Imatinib mesylate is a specific inhibitor of the Bcr-Abl kinase and has shown promising results in clinical studies. The structural relation between the Bcr-Abl oncogene and the tyrosine kinase inhibitor imatinib has recently been elucidated by an elegant crystal structure analysis, emphasizing the importance of dephosphorylated tyrosine 393 (Tyr393) in Bcr-Abl for access of the inhibitor to the kinase domain. By mutating this tyrosine to phenylalanine and thereby mimicking a constitutively dephosphorylated state, we now show that Ba/F3 cells transformed by this mutant demonstrate an increased sensitivity towards imatinib in vivo. This effect is not due to an impaired kinase activity of Bcr-Abl Y393F, since a synthetic substrate is phosphorylated with similar kinetics. Treatment of Ba/F3 cells transfected with Bcr-Abl wild type with a phosphatase inhibitor diminished the effect of imatinib, but did not influence the growth of Ba/F3 cells transfected with Bcr-AblY393F. The results support the findings of the crystal structure and indicate that Tyr393 indeed plays a significant role for the sensitivity of Bcr-Abl towards imatinib in vivo. These data implicate the regulation of Tyr393 phosphorylation as a potential mechanism of imatinib resistance.
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影响因子：
20.3
作者：
Bai, RY;Tao, OY;Duyster, J
通讯作者：
Duyster, J
影响因子：
56.9
作者：
Schindler, T;Bornmann, W;Kuriyan, J
通讯作者：
Kuriyan, J
一种新型的含有 SH2 的磷脂酰肌醇 3,4,5-三磷酸 5-磷酸酶 (SHIP2) 被组成型酪氨酸磷酸化，并与慢性粒细胞白血病祖细胞中的 src 同源和胶原基因 (SHC) 相关。
影响因子：
20.3
作者：
Wisniewski,D;Strife,A;Swendeman,S;Erdjument-Bromage,H;Geromanos,S;Kavanaugh,WM;Tempst,P;Clarkson,B
通讯作者：
Clarkson,B
基于绿色荧光蛋白的高效激酶底物。
DOI：
10.1006/abio.1998.2885
发表时间：
1999
期刊：
Analytical biochemistry.
影响因子：
--
作者：
Yang,F;Liu,Y;Bixby,SD;Friedman,JD;Shokat,KM
通讯作者：
Shokat,KM