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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mechanics of EGF Receptor/ErbB2 kinase activation revealed by luciferase fragment complementation imaging
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Mechanics of EGF Receptor/ErbB2 kinase activation revealed by luciferase fragment complementation imaging

机译：荧光素酶片段互补成像揭示EGF受体/ ErbB2激酶激活的机制

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摘要

Binding of EGF to its receptor induces dimerization of the normally monomeric receptor. Activation of its intracellular tyrosine kinase then occurs through the formation of an asymmetric kinase dimer in which one subunit, termed the "receiver" kinase, is activated by interaction with the other subunit, termed the "activator" kinase [Zhang, et al. (2006) Cell 125: 1137-1149]. Although there is significant experimental support for this model, the relationship between ligand binding and the mechanics of kinase activation are not known. Here we use luciferase fragment complementation in EGF receptor (EGFR)/ErbB2 heterodimers to probe the mechanics of ErbB kinase activation. Our data support a model in which ligand binding causes the c/s-kinase (the EGFR) to adopt the receiver position in the asymmetric dimer and to be activated first. If the EGF receptor is kinase active, this results in the phosphorylation of the trans-kinase (ErbB2). However, if the EGF receptor kinase is kinase dead, the ErbB2 kinase is never activated. Thus, activation of the kinases in the EGFR/ErbB2 asymmetric dimer occurs in a specific sequence and depends on the kinase activity of the EGF receptor.
机译：EGF与其受体的结合诱导正常单体受体的二聚化。然后其细胞内酪氨酸激酶的活化通过形成不对称激酶二聚体而发生，其中一个亚基称为“受体”激酶，通过与另一亚基相互作用而被激活，称为“活化剂”激酶[Zhang，et al。 （2006）Cell 125：1137-1149]。尽管对该模型有重要的实验支持，但配体结合与激酶激活机制之间的关系尚不清楚。在这里，我们在EGF受体（EGFR）/ ErbB2异二聚体中使用萤光素酶片段互补来探测ErbB激酶激活的机制。我们的数据支持一种模型，其中配体结合导致c / s激酶（EGFR）在不对称二聚体中采用受体位置并首先被激活。如果EGF受体具有激酶活性，则会导致转激酶（ErbB2）磷酸化。但是，如果EGF受体激酶被激酶杀死，则ErbB2激酶将永远不会被激活。因此，EGFR / ErbB2不对称二聚体中激酶的激活以特定序列发生，并取决于EGF受体的激酶活性。

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    Jennifer L. Macdonald-Obermann; David Piwnica-Worms; Linda J. Pike;

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    Departments of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110;

    Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110,Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110,The Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110,BRIGHT Institute, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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