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EGF stimulates the activation of EGF receptors and the selective activation of major signaling pathways during mitosis

机译：EGF刺激有丝分裂期间EGF受体的激活和主要信号通路的选择性激活

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Mitosis and epidermal growth factor (EGF) receptor (EGFR) are both targets for cancer therapy. The role of EGFR signaling in mitosis has been rarely studied and poorly understood. The limited studies indicate that the activation of EGFR and downstream signaling pathways is mostly inhibited during mitosis. However, we recently showed that EGFR is phosphorylated in response to EGF stimulation in mitosis. Here we studied EGF-induced EGFR activation and the activation of major signaling pathways downstream of EGFR during mitosis. We showed that EGFR was strongly activated by EGF during mitosis as all the five major tyrosine residues including Y992, Y1045, Y1068, Y1086, and Y1173 were phosphorylated to a level similar to that in the interphase. We further showed that the activated EGFR is able to selectively activate some downstream signaling pathways while avoiding others. Activated EGFR is able to activate PI3K and AKT2, but not AKT1, which may be responsible for the observed effects of EGF against nocodazole-induced cell death. Activated EGFR is also able to activate c-Src, c-Cbl and PLC-gamma 1 during mitosis. However, activated EGFR is unable to activate ERK1/2 and their downstream substrates RSK and Elk-1. While it activated Ras, EGFR failed to fully activate Raf-1 in mitosis due to the lack of phosphorylation at Y341 and the lack of dephosphorylation at pS259. We conclude that contrary to the dogma, EGFR is activated by EGF during mitosis. Moreover, EGFR-mediated cell signaling is regulated differently from the interphase to specifically serve the needs of the cell in mitosis. (C) 2015 Elsevier Inc. All rights reserved.
机译：有丝分裂和表皮生长因子（EGF）受体（EGFR）都是癌症治疗的目标。 EGFR信号转导在有丝分裂中的作用很少研究，了解甚少。有限的研究表明，在有丝分裂过程中，EGFR和下游信号通路的激活大部分受到抑制。但是，我们最近显示，在有丝分裂中，EGFR响应EGF刺激而被磷酸化。在这里，我们研究了有丝分裂期间EGF诱导的EGFR激活以及EGFR下游主要信号通路的激活。我们显示，在有丝分裂过程中，EGFR被EGF强烈激活，因为包括Y992，Y1045，Y1068，Y1086和Y1173在内的所有五个主要酪氨酸残基都被磷酸化至与中间相相似的水平。我们进一步表明，激活的EGFR能够选择性激活某些下游信号通路，同时避免其他信号通路。激活的EGFR能够激活PI3K和AKT2，但不能激活AKT1，这可能是观察到的EGF对诺考达唑诱导的细胞死亡的影响。激活的EGFR还能够在有丝分裂期间激活c-Src，c-Cbl和PLC-γ1。但是，激活的EGFR无法激活ERK1 / 2及其下游底物RSK和Elk-1。当它激活Ras时，由于在Y341缺少磷酸化和在pS259缺少去磷酸化，EGFR无法完全激活有丝分裂中的Raf-1。我们得出结论，与教条相反，EGFR在有丝分裂过程中被EGF激活。而且，EGFR介导的细胞信号传导与相间的调控不同，以专门满足有丝分裂中细胞的需求。 （C）2015 Elsevier Inc.保留所有权利。

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