Robustness of the bistable behavior of a biological signaling feedback loop

Abstract

Biological signaling networks comprised of cellular components including signaling proteins and small molecule messengers control the many cell function in responses to various extracellular and intracellular signals including hormone and neurotransmitter inputs, and genetic events. Many signaling pathways have motifs familiar to electronics and control theory design. Feedback loops are among the most common of these. Using experimentally derived parameters, we modeled a positive feedback loop in signaling pathways used by growth factors to trigger cell proliferation. This feedback loop is bistable under physiological conditions, although the system can move to a monostable state as well. We find that bistability persists under a wide range of regulatory conditions, even when core enzymes in the feedback loop deviate from physiological values. We did not observe any other phenomena in the core feedback loop, but the addition of a delayed inhibitory feedback was able to generate oscillations under rather extreme parameter conditions. Such oscillations may not be of physiological relevance. We propose that the kinetic properties of this feedback loop have evolved to support bistability and flexibility in going between bistable and monostable modes, while simultaneously being very refractory to oscillatory states.