EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization.
EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization.
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DOI：
10.1371/journal.pone.0023240
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Goldkorn T
中科院分区：
文献类型：
--
作者：
Filosto S;Khan EM;Tognon E;Becker C;Ashfaq M;Ravid T;Goldkorn T
晶体学研究让我们了解 ErbB 家族的受体酪氨酸激酶如何受到其生长因子配体的调节。 EGFR (ErbB1) 的构象变化在配体结合时发生，其中记录了仅配体介导的二聚化/激活模式。然而，这种二聚化/激活的教条因组成型活性非配体依赖性 EGFR 突变体的发现而彻底改变。此外，可能会发生其他不依赖于配体的激活机制。我们已经证明，由过氧化氢或香烟烟雾诱导的氧化应激（ox-应激）以不同于其配体 EGF 的方式激活 EGFR，从而诱导异常磷酸化以及 EGFR 运输和降解受损。在这里，我们证明 EGFR 的氧化应激激活是配体独立的，不会诱导“经典”受体二聚化，并且不会被酪氨酸激酶抑制剂 AG1478 抑制。因此，在氧化应激下，EGFR 出现了前所未有的、明显激活的状态。此外，这种激活机制是温度依赖性的，表明膜结构同时参与。我们提出，牛应激下神经酰胺的增加会破坏富含胆固醇的筏，导致 EGFR 重新定位到刚性的、富含神经酰胺的筏中。神经酰胺的增加也支持 EGFR 向核周区域的异常运输。因此，EGFR前所未有的激活构象可以通过氧应激下膜结构的同时改变来维持。
Crystallographic studies have offered understanding of how receptor tyrosine kinases from the ErbB family are regulated by their growth factor ligands. A conformational change of the EGFR (ErbB1) was shown to occur upon ligand binding, where a solely ligand-mediated mode of dimerization/activation was documented. However, this dogma of dimerization/activation was revolutionized by the discovery of constitutively active ligand-independent EGFR mutants. In addition, other ligand-independent activation mechanisms may occur. We have shown that oxidative stress (ox-stress), induced by hydrogen peroxide or cigarette smoke, activates EGFR differently than its ligand, EGF, thereby inducing aberrant phosphorylation and impaired trafficking and degradation of EGFR. Here we demonstrate that ox-stress activation of EGFR is ligand-independent, does not induce “classical” receptor dimerization and is not inhibited by the tyrosine kinase inhibitor AG1478. Thus, an unprecedented, apparently activated, state is found for EGFR under ox-stress. Furthermore, this activation mechanism is temperature-dependent, suggesting the simultaneous involvement of membrane structure. We propose that ceramide increase under ox-stress disrupts cholesterol-enriched rafts leading to EGFR re-localization into the rigid, ceramide-enriched rafts. This increase in ceramide also supports EGFR aberrant trafficking to a peri-nuclear region. Therefore, the EGFR unprecedented and activated conformation could be sustained by simultaneous alterations in membrane structure under ox-stress.
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影响因子：
4.8
作者：
Contreras, FX;Villar, AV;Goñi, FM
通讯作者：
Goñi, FM
影响因子：
64.5
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
影响因子：
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作者：
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影响因子：
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作者：
Chung BM;Raja SM;Clubb RJ;Tu C;George M;Band V;Band H
通讯作者：
Band H
DOI：
10.1016/j.bbrc.2010.03.052
发表时间：
2010-04-09
影响因子：
3.1
作者：
Ise, Nobuyuki;Omi, Kazuya;Goishi, Katsutoshi
通讯作者：
Goishi, Katsutoshi