Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site
Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site
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DOI：
10.1074/jbc.272.37.23247
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发表时间：
1997-09-12
影响因子：
4.8
通讯作者：
Guyer, CA
中科院分区：
文献类型：
--
作者：
Arteaga, CL;Ramsey, TT;Guyer, CA
受体二聚化对表皮生长因子受体(EGFR)酪氨酸激酶的信号传导至关重要，这种作用发生在受体的胞外结构域被配体或二价抗体结合后，其他受体结构域在二聚化中的作用尚不清楚，而且还没有直接干扰EGFR激动域诱导二聚体的例子，亚微摩尔浓度的AG-1478和AG-1517，特异性抑制EGFR激酶的喹唑啉类药物，在体外和完整的A431细胞中诱导的可逆性受体二聚物，与喹唑啉对受体激酶活性的抑制作用一致，形成的二聚体缺乏可检测到的Tyr(P)信号。对AG-1478和AG-1517有反应的野生型EGFR和ATP结合位点单点突变的受体以及野生型EGFR不能发生二聚化。这些结果表明，在没有受体配基和结合的情况下，在没有受体配基和结合的情况下，喹唑啉可以通过ATP位上的相互作用来诱导EGFR二聚化。在SKBR-3细胞中，喹唑啉诱导了无效的EGFR/ErbB-2异二聚体的形成，潜在地隔离了ErbB-2与ErbB家族其他辅助受体的相互作用。对喹唑啉与EGFR酪氨酸激酶域相互作用的结构研究应该能够分析与ATP位点结合和信号中断所需的受体特异性化学特征，这一策略可能适用于其他肿瘤细胞受体系统。
Receptor dimerization is critical for signaling by the epidermal growth factor receptor (EGFR) tyrosine kinase, This occurs after binding of the receptor's extracellular domain by ligand or bivalent antibodies, The role of other receptor domains in dimerization is less clear, and there are no examples of dimers induced by direct perturbation of the EGFR kinase domain, Submicromolar concentrations of AG-1478 and AG-1517, quinazolines specific for inhibition of the EGFR kinase, induced reversible receptor dimerization in vitro and in intact A431 cells, Consistent with the inhibitory effect of quinazolines on receptor kinase activity, the dimers formed lacked a detectable Tyr(P) signal. Quinazoline-induced EGFR dimerization was abrogated in vitro by ATP and the ATP analog adenyl-5'-yl imidodiphosphate, Receptors with a single-point mutation in the ATP binding site as well as wild-type EGFR with a covalent modification of the ATP site failed to dimerize in response to AG-1478 and AG-1517, These data suggest that EGFR dimerization can be induced by the interaction of quinazolines at the ATP site in the absence of receptor ligand binding, In SKBR-3 cells, the quinazolines induced the formation of inactive EGFR/ ErbB-2 heterodimers, potentially sequestering ErbB-2 from interacting with other coreceptors of the ErbB family, Structural studies of the quinazoline interaction with the EGFR tyrosine kinase domain should allow for an analysis of receptor-specific chemical features required for binding to the ATP site and disruption of signaling, a strategy that can be perhaps applied to other tumor cell receptor systems.