Kinase-mediated quasi-dimers of EGFR
Kinase-mediated quasi-dimers of EGFR
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DOI：
10.1096/fj.10-166199
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发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Yarden, Yosef
中科院分区：
文献类型：
--
作者：
Bublil, Erez M.;Pines, Gur;Yarden, Yosef
配体诱导的表皮生长因子受体（ErbB-1/EGFR）的二聚化涉及暴露细胞外二聚化界面的构象变化。胞质激酶结构域内的后续改变，最终导致酪氨酸磷酸化，不太清楚。我们的研究通过使用两种策略来解决这个问题：采用ErbB-3的嵌合受体方法，其有缺陷的激酶结构域被EGFR的相应部分取代。植入的全长激酶，不像它的亚结构域，赋予二聚化和催化。数据推断EGFR的激酶功能受到羧基尾的抑制;一旦远端移植到ErbB-3的异位尾，激酶结构域获得准二聚化和活化。为了尝试替代性地重折叠胞质尾区，我们的另一种方法采用激酶抑制剂。生物物理测量和共价交联分析表明，与识别非活性构象的化合物相反，靶向EGFR活性构象的抑制剂以类似于嵌合ErbB-3分子的方式诱导准二聚体。总的来说，这些观察揭示了激酶结构域介导的准二聚体，这是由一个自抑制羧基尾巴。基于这些观察结果，我们提出准二聚体先于配体诱导的完全活性二聚体的形成，其通过细胞外和细胞内受体-受体相互作用稳定。Bublil，E. M.，派恩斯，帕特尔，G.，Fruhouth，G.，Ng，T.，约瑟夫·亚登激酶介导的EGFR准二聚体。FASEB J.24，4744-4755（2010）。www.fasebj.org
Ligand-induced dimerization of the epidermal growth factor receptor (ErbB-1/EGFR) involves conformational changes that expose an extracellular dimerization interface. Subsequent alterations within the cytoplasmic kinase domain, which culminate in tyrosine phosphorylation, are less understood. Our study addressed this question by using two strategies: a chimeric receptor approach employed ErbB-3, whose defective kinase domain was replaced by the respective part of EGFR. The implanted full-length kinase, unlike its subdomains, conferred dimerization and catalysis. The data infer that the kinase function of EGFR is restrained by the carboxyl tail; once grafted distally to the ectopic tail of ErbB-3, the kinase domain acquires quasi-dimerization and activation. In an attempt to alternatively refold the cytoplasmic tail, our other approach employed kinase inhibitors. Biophysical measurements and covalent cross-linking analyses showed that inhibitors targeting the active conformation of EGFR, in contrast to a compound recognizing the inactive conformation, induce quasi-dimers in a manner similar to the chimeric ErbB-3 molecule. Collectively, these observations unveil kinase domain-mediated quasi-dimers, which are regulated by an autoinhibitory carboxyl tail. On the basis of these observations, we propose that quasi-dimers precede formation of ligand-induced, fully active dimers, which are stabilized by both extracellular and intracellular receptor-receptor interactions.-Bublil, E. M., Pines, G., Patel, G., Fruhwirth, G., Ng, T., Yosef Yarden. Kinase-mediated quasi-dimers of EGFR. FASEB J. 24, 4744-4755 (2010). www.fasebj.org