The effects of cascade length, kinetics and feedback loops on biological signal transduction dynamics in a simplified...

How intracellular signals are propagated with appropriate strength, duration and fidelity over time is poorly understood. To address these issues, intracellular signal transduction was studied both analytically and numerically using a simplified cascade model. The main observations can be summarized as follows: when the response kinetics is of the Michaelis-Menten type, the signal strength will always reach the same magnitude as the cascade length increases, regardless of the type of stimulus applied (i.e. either continuous or unitary pulse). However, when the response kinetics is of the Hill type (Hill coefficient >1), there exists a stimulation threshold. If the stimulus is below the threshold, the signal decays toward zero; in contrast, if the stimulus is above the threshold, the signal amplitude reaches a nonzero steady state. The time taken for the signal to proceed through the cascade increases as the half-maximum point, or Hill coefficient, increases, whereas the duration of the output signal at the end of the cascade decreases as the half-maximum point increases. In the presence of positive feedback, the stimulation threshold increases; under these conditions, the feedback strength necessary for bistability changes (with power-law characteristics) inversely related to the length of the cascade. In the presence of negative feedback, oscillations are induced when the Hill coefficient is greater than 1 and the cascade has more than two steps. Likewise, the feedback strength required to generate oscillations changes (again with power-law characteristics) inversely with the length of the cascade.