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Sci. Signal., 27 July 2010
Vol. 3, Issue 132, p. ra56
[DOI: 10.1126/scisignal.2000810]

RESEARCH ARTICLES

Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics

Kazuhiro A. Fujita1, Yu Toyoshima2, Shinsuke Uda2, Yu-ichi Ozaki2, Hiroyuki Kubota2, and Shinya Kuroda1,2*

1 Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Kshiwanoha 5-1-5, Kashiwa, Chiba 277-8568, Japan.
2 Department of Biophysics and Biochemistry, Graduate School of Science, CREST, Japan Science and Technology Agency, University of Tokyo, Hongo 7-3-1, Bunkyo-ku,Tokyo 113-0033, Japan.

Abstract: 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.

* To whom correspondence should be addressed. E-mail: skuroda{at}bi.s.u-tokyo.ac.jp

Citation: K. A. Fujita, Y. Toyoshima, S. Uda, Y.-i. Ozaki, H. Kubota, S. Kuroda, Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics. Sci. Signal. 3, ra56 (2010).

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