Limits to the rate of information transmissionthrough MAPK pathway

Abstract

Two important signaling pathways of NF-{kappa}B and ERK transmit merely one bit of information about the level of extracellular stimulation. It is thus unclear how such systems can coordinate complex cell responses to external cues. Here, we analyze information transmission in the MAPK/ERK pathway that features relaxation oscillations and responds to EGF by pulses of activated ERK. Based on an experimentally verified computational model of the MAPK/ERK pathway, we demonstrate that when input sequences of EGF pulses are transcoded to output sequences of ERK activity pulses, transmitted information increases nearly linearly with time. Moreover, the information channel capacity C (defined as the upper limit of information that can be transmitted over a sufficiently long time t, divided by t), is not limited by the bandwidth B = 1/{tau}, where {tau} {approx} 1 hour is the relaxation time. Specifically, when input is provided in the form of sequences of short binary EGF pulses separated by varying intervals that are multiples of {tau}/n (but are not shorter than {tau}), then for n = 2, C {approx} 1.39 bit/hour; and for n = 4, C {approx} 1.86 bit/hour. We hypothesize that the primary mode of operation of the MAPK pathway is to translate extracellular growth factor \"bursts\" into precisely timed intracellular ERK \"spikes\" of a predefined amplitude. Such pulse-interval transcoding allows to relay more information than the amplitude-amplitude transcoding considered previously for the ERK and NF-{kappa}B pathways.\n\nAuthor summaryTo coordinate their actions, cells communicate with each other by sending, receiving, and interpreting cytokine signals. Cells recognize chemical identity of signaling molecules and process quantitative and temporal properties of stimulation: amplitude, duration, or frequency. Previous studies indicated that the MAPK pathway transmits about one bit of information about the amplitude (concentration) of a stimulating cytokine, EGF. Sending more information may be enabled by temporal signal modulation. Here, we use the conceptual framework of information theory to support a hypothesis that the MAPK pathway, analyzed as a noisy information channel, reaches maximum information transmission rate when receiving sequences of EGF pulses that are transcoded to sequences of activity pulses of an effector kinase of the pathway, ERK. Since the pathway resetting time is about 1 hour, one could expect that--when sending EGF pulses of \"0\" or \"1\" amplitude every hour--the pathway is able transmit up to 1 bit per hour. We show, however, that when EGF pulses are separated by intervals that are not shorter than 1 hour and are multiples of 15 min (60, 75, 90 min, etc.), information rate can be nearly 2 bits per hour. We hypothesize that high information rate is necessary to control cell proliferation and motility.