Ligand-Independent EGFR Signaling.
Ligand-Independent EGFR Signaling.
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DOI：
10.1158/0008-5472.can-15-0989
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发表时间：
2015-09-01
期刊：
影响因子：
11.2
通讯作者：
Habib AA
中科院分区：
文献类型：
--
作者：
Guo G;Gong K;Wohlfeld B;Hatanpaa KJ;Zhao D;Habib AA
由于EGFR野生型（EGFRwt）过表达或突变型EGFR的存在，EGFR的组成性激活在癌症中很常见。已经深入研究了胶质母细胞瘤中组成型活性NSCLC EGFR突变体或EGFRvIII突变体的信号传导，并且下游信号是已知的。通常，当EGFRwt暴露于配体时，其被激活，导致典型信号如ERK和Akt的激活。EGFRwt也成为酪氨酸磷酸化和组成型激活无配体时，它是过表达，但下游信号是不清楚的。最近的研究已经确定了一种非规范形式的信号传导，其仅在不存在配体的情况下由EGFRwt触发，不涉及ERK或Akt活化，而是导致转录因子IRF3的活化。配体的添加关闭IRF3依赖性转录并激活ERK和Akt。因此，EGFR根据配体的存在触发不同且互斥的信号传导网络。此外，非典型的EGFRwt信号传导可能影响对癌症治疗的反应。此外，也有报告的协同和拮抗作用的配体依赖性EGFRwt和EGFRvIII信号之间的相互作用，在这里，我们讨论配体非依赖性EGFR信号转导的致癌突变体和EGFRwt，并审查EGFRwt和EGFRvIII之间的相互作用。
Constitutive activation of the EGFR is common in cancer due to EGFR wild type (EGFRwt) overexpression or the presence of mutant EGFR. Signaling by constitutively active NSCLC EGFR mutants or the EGFRvIII mutant in glioblastoma has been studied intensively and the downstream signals are known. Normally, the EGFRwt is activated when it is exposed to ligand resulting in activation of canonical signals such as ERK and Akt. The EGFRwt also becomes tyrosine phosphorylated and constitutively activated without ligand when it is overexpressed, but downstream signals are unclear. Recent studies have identified a non-canonical form of signaling triggered by EGFRwt exclusively in the absence of ligand that does not involve ERK or Akt activation but, instead, results in activation of the transcription factor IRF3. Addition of ligand turns off IRF3 dependent transcription and activates ERK and Akt. Thus, the EGFR triggers distinct and mutually exclusive signaling networks depending on the presence of ligand. Furthermore, non-canonical EGFRwt signaling may influence response to treatment in cancer. Also, there are reports of both synergistic and antagonistic interactions between ligand-dependent EGFRwt and EGFRvIII signaling, Here, we discuss ligand-independent EGFR signal transduction by oncogenic EGFR mutants and EGFRwt, and review the interplay between EGFRwt and EGFRvIII.