2010年7月
Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics
SCIENCE SIGNALING
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- 巻
- 3
- 号
- 132
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1126/scisignal.2000810
- 出版者・発行元
- AMER ASSOC ADVANCEMENT SCIENCE
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.
- リンク情報
- ID情報
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- DOI : 10.1126/scisignal.2000810
- ISSN : 1937-9145
- eISSN : 1937-9145
- Web of Science ID : WOS:000280403500002