Press Releases
Jul. 28, 2010

Analysis of signal processing mechanism of cellular signal transduction

— Clinical anti-cancer drug triggers a paradoxical downstream response —
Presenters
  • Kazuhiro A. Fujita (Department of Computational Biology, University of Tokyo)
  • Yu Toyoshima (Department of Biophysics and Biochemistry, University of Tokyo)
  • Shinsuke Uda (Department of Biophysics and Biochemistry, University of Tokyo)
  • Yu-ichi Ozaki (Department of Biophysics and Biochemistry, University of Tokyo)
  • Hiroyuki Kubota (Department of Biophysics and Biochemistry, University of Tokyo)
  • Shinya Kuroda (Department of Biophysics and Biochemistry, University of Tokyo)

Abstract

Figure 1

Fig. 1: Analogy of signal processing mechanims in artificial and cellular systems

In artificial systems such as radio, radio transmits the signal of temporal patterns (frequency and amplitude) of electromagnetic waves into air vibration. We found that biological systems such as intracellular signal transduction, signal transduction pathways transmit specific information of temporal patterns of receptor phosphorylation (i.e. low-frequency wave) into downstream of the pathway.

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 in the absence of the inhibitor. This suggests that an EGFR inhibitor can potentially act as a downstream activator of some effectors.

Paper information

Fujita, K.A., Toyoshima, Y., Uda, S., Ozaki, Y., Kubota, H., and Kuroda, S (2010)
Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics, Science Signaling, 3, (132), ra56, doi: 10.1126/scisignal.2000810

Figure 2

Fig. 2: Frequency response analysis of intracellular signal transduction

We modeled the Akt signaling pathway, which regulate cell growth. We decomposed the time course of the upstream and the downstream molecules into sine waves, and obtained the amplitude spectra. By dividing of the amplitude spectra of the downstream by that of the upstream, we obtained the frequency-dependent gain, which indicates the transmission efficiency of the pathway.

Figure 3

Fig. 3: Decoupling of receptor and downstream signals by the low-pass filter characteristics.

We found 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. This allowed us to predict and validate that clinically used anti-cancer drug paradoxically induced a strong response compared with its abasence.