Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability

Cell signaling systems that contain positive-feed back loops or double-negative feedback loops can, in principle, convert graded inputs into switch-like, irreversible responses. Systems of this sort are termed 'bistable'. Recently, several groups have engineered artificial bistable systems into Escherichia coli and Saccharomyces cerevisiae, and have shown that the systems exhibit interesting and potentially useful properties. In addition, two naturally occurring signaling systems, the p42 mitogen-activated protein kinase and c-Jun amino-terminal kinase pathways in Xenopus oocytes, have been shown to exhibit bistable responses. Here we review the basic properties of bistable circuits, the requirements for construction of a satisfactory bistable switch, and the recent progress towards constructing and analysing bistable signaling systems.