A myristoyl/phosphotyrosine switch regulates c-Abl
A myristoyl/phosphotyrosine switch regulates c-Abl
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DOI：
10.1016/s0092-8674(03)00191-0
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发表时间：
2003-03-21
期刊：
影响因子：
64.5
通讯作者：
Superti-Furga, G
中科院分区：
文献类型：
--
作者：
Hantschel, O;Nagar, B;Superti-Furga, G
c-Abl酪氨酸激酶受机制抑制，但机制尚不清楚。Bcr-Abl癌蛋白中这些机制的破坏导致几种形式的人类白血病。我们发现，像Src激酶，c-Abl 1b被磷酸酪氨酸配体激活。配体活化的c-Abl对抗癌药物STI-571/Gleevec/imatinib（STI-571）特别敏感。Src激酶中的SH 2结构域-磷酸化尾部相互作用在c-Abl中被N-末端肉豆蔻酰修饰与激酶结构域的分子内接合功能性取代。结合结构分析的功能研究定义了c-Abl中的肉豆蔻酰/磷酸酪氨酸开关，其调节SH 2结构域的对接和可及性。这一机制为观察到的酪氨酸磷酸化蛋白对c-Abl的细胞活化、c-Abl的细胞内移动性提供了解释，并为STI-571的作用机制提供了新的见解。
The c-Abl tyrosine kinase is inhibited by mechanisms that are poorly understood. Disruption of these mechanisms in the Bcr-Abl oncoprotein leads to several forms of human leukemia. We found that like Src kinases, c-Abl 1b is activated by phosphotyrosine ligands. Ligand-activated c-Abl is particularly sensitive to the anti-cancer drug STI-571/Gleevec/imatinib (STI-571). The SH2 domain-phosphorylated tail interaction in Src kinases is functionally replaced in c-Abl by an intramolecular engagement of the N-terminal myristoyl modification with the kinase domain. Functional studies coupled with structural analysis define a myristoyl/phosphotyrosine switch in c-Abl that regulates docking and accessibility of the SH2 domain. This mechanism offers an explanation for the observed cellular activation of c-Abl by tyrosine-phosphorylated proteins, the intracellular mobility of c-Abl, and it provides new insights into the mechanism of action of STI-571.