Kinase cascades are binary to the bone

Like electronic relays, many biological signaling pathways are bistable, able to turn “on” or “off” in response to a stimulus, but unstable in intermediate positions. The conventional view is that bistable cellular signaling requires a distinct positive or double-negative feedback signal; but on page 353, Markevich et al. prove that it does not. Instead, signaling pathways like the common MAPK cascade are intrinsically bistable, suggesting that feedback loops function primarily to increase the repertoire and flexibility of cellular responses.

The authors performed a mathematical analysis of a generic MAPK phosphorylation/dephosphorylation cycle, in which MAPK can be phosphorylated or dephosphorylated on two sites. Their assumptions were that the monophosphorylated and diphosphorylated forms of MAPK compete for either kinase or phosphatase, and that the enzymes are nonprocessive. Under these conditions, the equations reveal bistability in the absence of a distinct feedback system. Instead, the competition of substrates for enzymes automatically reinforces a stable “on” or “off” state and makes intermediate states unstable.

Nonetheless, the ubiquity of biochemical feedback loops implies that they serve some purpose. One possibility is that the combination of intrinsic bistability and a feedback loop could confer multistability, allowing systems like the MAPK cascade to signal varying degrees of “on.” ▪