Abstract
Cells use biological signal transduction pathways to respond to environmental stimuli and the behavior of many cell types depends on precise sensing and transmission of external information. A notable property of signal transduction that was characterized in the Saccharomyces cerevisiae yeast cell and many mammalian cells is the alignment of dose-response curves. It was found that the dose response of the receptor matches closely the dose responses of the downstream. This dose-response alignment (DoRA) renders equal sensitivities and concordant responses in different parts of signaling system and guarantees a faithful information transmission. The experimental observations raise interesting questions about the nature of the information transmission through DoRA signaling networks and design principles of signaling systems with this function. Here, we performed an exhaustive computational analysis on network architectures that underlie the DoRA function in simple regulatory networks composed of two and three enzymes. The minimal circuits capable of DoRA were examined with Michaelis-Menten kinetics. Several motifs that are essential for the dynamical function of DoRA were identified. Systematic analysis of the topology space of robust DoRA circuits revealed that, rather than fine-tuning the network's parameters, the function is primarily realized by enzymatic regulations on the controlled node that are constrained in limiting regions of saturation or linearity.
Highlights
Cells use signal transduction pathways to respond to environmental stimuli
Full-space screening for dose-response alignment (DoRA) circuits To identify simple network topologies that can achieve the function of DoRA, we first carry out an extensive screening for dose-response aligned circuits in all regulatory networks that are composed of two and three interacting enzymes (Figure 2a)
To clarify structure features in the functional networks composed of three nodes, we focused on 633 DoRA circuits that have achieved DoRA function more than 15 times when 10,000 parameter sets are sampled
Summary
Cells use signal transduction pathways to respond to environmental stimuli. Receptors on cell surface sense the signal, trigger subsequent intracellular signaling cascades, and eventually create a change either in the activity of enzymes in the cytoplasm or in gene expressions in the nucleus. In a class of cellular signaling systems, experimental studies of the input-output properties demonstrate that the systems show a notable feature named dose-response alignment (DoRA): the dose-response curve of receptor occupancy aligns closely with dose-response curves of downstream responses [1] (Figure 1a). Evidences for such DoRA property were previously demonstrated in many mammalian cell signaling systems. Extensive DoRAs were observed from the upstream to the downstream of the pathway: the receptor occupancy is aligned with the G-protein activation/dissociation, the accumulated amount of pheromone-activated Ste, pheromone-inducible gene expressions, and the cell-cycle arrest, despite that there are many intermediate signaling events in the system [1,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
