Mechanisms generating ultrasensitivity, bistability, and oscillations in signal transduction

Abstract

Stimulus-response curves of signal transduction cascades are often nonlinear; take, for example, sigmoidal curves. Such sigmoidal curves are frequently termed ultrasensitive, as small alterations in the stimulus can elicit large changes in the response. This chapter shall review the importance of ultrasensitivity in signal transduction, with a focus on the activation of the mitogen-activated protein kinase (MAPK) cascade. The major mechanisms that generate ultrasensitivity (Figure 1) are introduced. In particular, zero-order kinetics and multisite phosphorylation are discussed. Ultrasensitive signaling cascades equipped with positive or negative feedback loops may exhibit complex dynamic behavior. The large body of theory for effects of feedbacks shall be reviewed in this chapter. It is discussed that bistability can emerge from ultrasensitivity in conjunction with positive feedback, whereas adaptation, oscillations, and, surprisingly, highly linear response can arise with negative feedback. © 2007 Humana Press Inc.