Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics
Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics
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DOI：
10.1126/scisignal.2000810
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发表时间：
2010-07-27
影响因子：
7.3
通讯作者：
Kuroda, Shinya
中科院分区：
文献类型：
--
作者：
Fujita, Kazuhiro A.;Toyoshima, Yu;Kuroda, Shinya
在细胞信号转导中，外部刺激中的信息在信号分子的活动中以时间模式编码；例如，刺激的脉冲可在信号分子中产生递增的响应或产生脉动响应。在这里，我们展示了参与细胞生长的Akt通路如何特异性地将上游信号中包含的时间信息传递给下游效应器。在实验结果的基础上，我们在PC12细胞中模拟了表皮生长因子（EGF）依赖性Akt通路。我们得到了反直觉的结果，表明受体和下游效应物磷酸化的峰幅大小是解耦的；弱的、持续的EGF受体（EGFR）磷酸化，而不是强的、短暂的磷酸化，强烈诱导了Akt下游分子核糖体蛋白S6的磷酸化。通过频率响应分析，我们发现三组分Akt通路具有低通滤波器的特性，这一特性可以解释受体磷酸化的峰值振幅与下游效应物的峰值振幅的解耦。此外，我们发现作为抗癌药物的EGFR抑制剂拉帕替尼（lapatinib）可以将强烈的、短暂的Akt磷酸化转化为微弱的、持续的Akt磷酸化，并且由于Akt通路的低通过滤特性，这导致S6磷酸化比没有抑制剂时更强烈。因此，EGFR抑制剂可以潜在地作为一些效应器的下游激活剂。
In cellular signal transduction, the information in an external stimulus is encoded in temporal patterns in the activities of signaling molecules; for example, pulses of a stimulus may produce an increasing response or may produce pulsatile responses in the signaling molecules. Here, we show how the Akt pathway, which is involved in cell growth, specifically transmits temporal information contained in upstream signals to downstream effectors. We modeled the epidermal growth factor (EGF)-dependent Akt pathway in PC12 cells on the basis of experimental results. We obtained counterintuitive results indicating that the sizes of the peak amplitudes of receptor and downstream effector phosphorylation were decoupled; weak, sustained EGF receptor (EGFR) phosphorylation, rather than strong, transient phosphorylation, strongly induced phosphorylation of the ribosomal protein S6, a molecule downstream of Akt. Using frequency response analysis, we found that a three-component Akt pathway exhibited the property of a low-pass filter and that this property could explain decoupling of the peak amplitudes of receptor phosphorylation and that of downstream effectors. Furthermore, we found that lapatinib, an EGFR inhibitor used as an anticancer drug, converted strong, transient Akt phosphorylation into weak, sustained Akt phosphorylation, and, because of the low-pass filter characteristics of the Akt pathway, this led to stronger S6 phosphorylation than occurred in the absence of the inhibitor. Thus, an EGFR inhibitor can potentially act as a downstream activator of some effectors.