Limits to the rate of information transmission through MAPK pathway

Abstract

Two important signaling pathways of NF-κB 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/τ, where τ ≈ 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 τ/n (but are not shorter than τ), then for n = 2, C ≈ 1.39 bit/hour; and for n = 4, C ≈ 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-κB pathways. Author 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.

Information transmission from NFkB signaling dynamics to gene expression

“…full timeseries) of NFkB into the dynamics of gene expression. It will be interesting to analyze what aspects of the dynamic patterns are more meaningful using either a features based approach [56] or through the use of information transmission rate [57].…”

“…However, a high level of measurement error and a small sample size preclude an analysis of the reliability of information transmission accuracy from signaling dynamics into gene expression processes. Theoretical work on this question was more extensive [19,[55][56][57][58]. However past work based the analysis on specific dynamic features (e.g.…”

Mapping the dynamic transfer functions of epigenome editing

“…Information theory also provides a theoretical basis to move from phenomenological frameworks of dose-dependent gene responses that assumes continuous and graded control over gene expression levels, to thinking about true information transmission more rigorously. Interestingly, we and others (Billing et al, 2019;Cheong et al, 2011;Dubuis et al, 2013;Grabowski et al, 2019;Hansen and O'Shea, 2015;Harton and Batchelor, 2017;Jetka et al, 2019;Selimkhanov et al, 2014;Tkacik et al, 2009;Tudelska et al, 2017;Uda et al, 2013) have shown that these biological unit processes have relatively low information content of less than 1.5 bits (i.e. ~3 states).…”

“…This reliability is characterized by the noisiness of gene expression. Gene expression noise is an important and inherently stochastic process due to the low copy number of genes (Eldar and Elowitz, 2010;Elowitz and Leibler, 2000;Maheshri and O'Shea, 2007) and, together with cell-to-cell variability in general cellular components, creates a distribution of single-cell outputs for each unique input (Elowitz and Leibler, 2000;Grabowski et al, 2019;Gregor et al, 2007;Rosenfeld et al, 2005;Tkacik et al, 2009). As noise plays an important role in determining the reliability of a system and the fidelity of transmitted information, we first quantified how noise in our system was affected by F, A, and PW modulation.…”

Emergence of first strains of SARS-CoV-2 lineage B.1.1.7 in Romania

“…Namely, the N50Y mutation of S gene significantly increases the force and number of interactions with the human receptor ACE2 [14,15]. The two aminoacid deletion at positions 69-70 in the same S gene leads to systematically biased diagnostic tests and doubles the reproductive advantage and numbers of the virus [16]. Furthermore, the P681H mutation of S protein might influence the cleavage of S protein through effest on S1/S2 subunits furin cleavage site [17].…”