Robustness of the bistable behavior of a biological signaling feedback loop

Biological signaling networks comprised of cellular components including si gnaling proteins and small molecule messengers control the many cell functi on in responses to various extracellular and intracellular signals includin g hormone and neurotransmitter inputs, and genetic events. Many signaling p athways have motifs familiar to electronics and control theory design. Feed back 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 bis table under physiological conditions, although the system can move to a mon ostable state as well. We find that bistability persists under a wide range of regulatory conditions, even when core enzymes in the feedback loop devi ate from physiological values. We did not observe any other phenomena in th e core feedback loop, but the addition of a delayed inhibitory feedback was able to generate oscillations under rather extreme parameter conditions. S uch oscillations may not be of physiological relevance. We propose that the kinetic properties of this feedback loop have evolved to support bistabili ty and flexibility in going between bistable and monostable modes, while si multaneously being very refractory to oscillatory states. (C) 2001 American Institute of Physics.