Abstract
A most important property of biochemical systems is robustness. Static robustness, e.g., homeostasis, is the insensitivity of a state against perturbations, whereas dynamics robustness, e.g., homeorhesis, is the insensitivity of a dynamic process. In contrast to the extensively studied static robustness, dynamics robustness, i.e., how a system creates an invariant temporal profile against perturbations, is little explored despite transient dynamics being crucial for cellular fates and are reported to be robust experimentally. For example, the duration of a stimulus elicits different phenotypic responses, and signaling networks process and encode temporal information. Hence, robustness in time courses will be necessary for functional biochemical networks. Based on dynamical systems theory, we uncovered a general mechanism to achieve dynamics robustness. Using a three-stage linear signaling cascade as an example, we found that the temporal profiles and response duration post-stimulus is robust to perturbations against certain parameters. Then analyzing the linearized model, we elucidated the criteria of how such dynamics robustness emerges in signaling networks. We found that changes in the upstream modules are masked in the cascade, and that the response duration is mainly controlled by the rate-limiting module and organization of the cascade's kinetics. Specifically, we found two necessary conditions for dynamics robustness in signaling cascades: 1) Constraint on the rate-limiting process: The phosphatase activity in the perturbed module is not the slowest. 2) Constraints on the initial conditions: The kinase activity needs to be fast enough such that each module is saturated even with fast phosphatase activity and upstream information is attenuated. We discussed the relevance of such robustness to several biological examples and the validity of the above conditions therein. Given the applicability of dynamics robustness to a variety of systems, it will provide a general basis for how biological systems function dynamically.
Author Summary Cells use signaling pathways to transmit information received on its membrane to DNA,and many important cellular processes are tied to signaling networks. Past experiments have shown that cells’ internal signaling networks are sophisticated enough to process and encode temporal information such as the length of time a ligand is bound to a receptor. However, little research has been done to verify whether information encoded onto temporal profiles can be made robust. We examined mathematical models of linear signaling networks and found that the relaxation of the response to a transient stimuli can be made robust to certain parameter fluctuations. Robustness is a key concept in 1/15 biological systems it would be disastrous if a cell could not operate if there was as light change in its environment or physiology. Our research shows that such dynamics robustness does emerge in linear signaling cascades, and we outline the design principles needed to generate such robustness. We discovered that two conditions regarding the speed of the internal chemical reactions and concentration levels are needed to generate dynamics robustness.
Footnotes
↵* kaneko{at}complex.c.u-tokyo.ac.jp
