Mathematical and Computational Analysis of Adaptation via Feedback Inhibition in Signal Transduction Pathways

Abstract

We perform a systematic analysis of mechanisms of feedback regulation that underlie short-term adaptation in intracellular signaling systems. Upon receiving an external cue, these systems generate a transient response that quickly returns to basal levels even if the stimulus persists. Signaling pathways capable of short-term adaptation are found in systems as diverse as the high osmolarity response of yeast, gradient sensing in Dictyostelium, and the cytokine response in vertebrates. Using mathematical analysis and computational experiments, we compare different feedback architectures in terms of response amplitude and duration, ability to adapt, and response to variable stimulus levels. Our analysis reveals three important features of these systems: 1), multiple step signaling cascades improve sensitivity to low doses by an effect distinct from signal amplification; 2), some feedback architectures act as signal transducers converting stimulus strength into response duration; and 3), feedback deactivation acts as a dose-dependent switch between transient and sustained responses. Finally, we present characteristic features for each form of feedback regulation that can aid in their identification.

Adaptive response by state-dependent inactivation

“…While biological feedback is most often discussed in the strict sense of direct interaction between upstream and downstream components of a pathway (30,31), in the wide sense it is a flow of information from a system output back to its input. Such a flow can be an emergent property of system dynamics without physical interaction between output and input.…”

Aptamer-Enabled Manipulation of the Hsp70 Chaperone System Suggests a Novel Strategy for Targeted Ubiquitination

“…In this feedback system, CHIP is both the signaling molecule (executor of ubiquitination) and also the direct negative regulator of an upstream pathway component (Hsp70 activity). Therefore, both the signaling and the feedback occur on the same timescale, resulting in a strong negative feedback system that cannot produce a transient response [47]. So, a stimulus such as stress or heat shock that causes proteins to misfold and activates the Hsp70 chaperone system would not result in an instant and transient surge in CHIP-mediated ubiquitination of Hsp70 substrates.…”

“…So, a stimulus such as stress or heat shock that causes proteins to misfold and activates the Hsp70 chaperone system would not result in an instant and transient surge in CHIP-mediated ubiquitination of Hsp70 substrates. Instead, it would result in a slow increase in ubiquitination, which would persist as long as the stimulus is present [47]. Such a mechanism would prevent an outburst of chaperone substrate degradation, which is costly in energy, but at the same time allows for sustained degradation of extensively misfolded proteins, which are likely to have a stronger interaction with Hsp70.…”

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

“…Immune response is partly regulated through the natural death of immune cells, but one of the dominant regulatory mechanisms that is often less scrutinized is the presence of feedback and FFLs 2. Feedback and FFLs have been shown to play a crucial role in shaping response‐adaptation in several cellular systems and signaling pathways, such as MEK/ERK, Akt/mTOR, JAK/STAT, and other kinase cascades 3, 4, 5, 6, 7. They have also been shown to control the cell fate during early development 8.…”