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

Sci. Signal.  27 Jul 2010:
Vol. 3, Issue 132, pp. ra56
DOI: 10.1126/scisignal.2000810

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Converting Weak into Strong

Signaling pathways have complex kinetics, amplifying a signal, delaying a signal, or filtering out a signal. Fujita et al. performed kinetic analysis of the phosphorylation of three components in the epidermal growth factor receptor (EGFR) pathway—EGFR, the downstream kinase Akt, and the Akt effector ribosomal protein S6—and found that the strongest phosphorylation of the downstream effector occurred with weak, but sustained, receptor activation. Mathematical analysis indicated that Akt served as a low-pass filter to convert weak, sustained receptor signals into strong effector signals and to limit the transmission of strong, transient receptor signals. Exposure of cells to a clinically used inhibitor of the EGFR triggered a paradoxically strong phosphorylation of S6, suggesting that inhibitor data must be analyzed carefully in light of this low-pass filter characteristic.