The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
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DOI：
10.1016/j.yexcr.2008.07.031
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发表时间：
2009-02-15
影响因子：
3.7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Bose R;Zhang X
表皮生长因子受体（EGFR）及其家族成员ErbB 2、ErB 3和ErB 4是受体酪氨酸激酶，其将信号发送到细胞中以调节许多关键过程，包括发育、组织稳态和肿瘤发生。这些受体的信号传导的中心是它们的细胞内激酶结构域，其通过配体诱导的受体二聚化激活并磷酸化C-末端尾中的几个酪氨酸残基。磷酸化的尾巴然后招募其他信号分子并将信号传递到下游途径。ErbB激酶结构域的自抑制，激活和反馈抑制机制的模型已经出现了一些最近的结构研究。同时，最近的临床研究揭示了特异性ErbB激酶突变与激酶抑制剂药物反应性之间的关系。我们将回顾ErbB激酶结构域的这些调节机制，并从结构的角度讨论激酶抑制剂的结合特异性和在癌症患者中发现的激酶结构域突变的影响。
Epidermal growth factor receptor (EGFR) and its family members, ErbB2, ErB3 and ErB4, are receptor tyrosine kinases which send signals into the cell to regulate many critical processes including development, tissue homeostasis, and tumorigenesis. Central to the signaling of these receptors is their intracellular kinase domain, which is activated by ligand-induced dimerization of the receptor and phosphorylates several tyrosine residues in the C-terminal tail. The phosphorylated tail then recruits other signaling molecules and relays the signal to downstream pathways. A model of the autoinhibition, activation and feedback inhibition mechanisms for the ErbB kinase domain has emerged from a number of recent structural studies. Meanwhile, recent clinical studies have revealed the relationship between specific ErbB kinase mutations and the responsiveness to kinase inhibitor drugs. We will review these regulation mechanisms of the ErbB kinase domain, and discuss the binding specificity of kinase inhibitors and the effects of kinase domain mutations found in cancer patients from a structural perspective.
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