Abstract Positive feedback loops are common regulatory elements in metabolic and protein signalling pathways. The length of such feedback loops deter- mines stability and sensitivity to network perturbations. Here we provide a mathematical analysis of arbitrary length positive feedback loops with protein production and degradation. These loops serve as an abstraction of typical regulation patterns in protein signalling pathways. We first perform a steady state analysis and, independently of the chain length, identify exactly two steady states that represent either biological activity or inactivity. We thereby provide two formulas for the steady state protein concentrations as a function of feedback length, strength of feedback, as well as protein production and degradation rates. Using a control theory approach, analysing the frequency response of the linearisation of the system and exploiting the Small Gain The- orem, we provide conditions for local stability for both steady states. Our results demonstrate that, under some parameter relationships, once a biolog- ical meaningful on steady state arises, it is stable, while the off steady state, where all proteins are inactive, becomes unstable. We apply our results to a three-tier feedback of caspase activation in apoptosis and demonstrate how an intermediary protein in such a loop may be used as a signal amplifier within the cascade. Our results provide a rigorous mathematical analysis of positive feedback chains of arbitrary length, thereby relating pathway structure and stability.

Url http://eprints.maynoothuniversity.ie/6963/

Collections Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Research Institutes
Ireland -> Maynooth University -> Type = Article
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Research Institutes: Hamilton Institute
Ireland -> Maynooth University -> Status = Published
Ireland -> Maynooth University -> Open Access DRIVERset