Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades

TLDR

MAPK cascades can function as bistable switches, and although positive feedback loops are often considered necessary, they are not required for bistability. The study aims to demonstrate that bistability and hysteresis can arise without imposed feedback regulation. This occurs through a distributive kinetic mechanism of two‑site MAPK phosphorylation and dephosphorylation. The kinetic properties of MEK and MKP3 satisfy the conditions for a bistable switch at a single MAPK cascade level, suggesting that multisite covalent modification broadly controls protein activity via bistability.

Abstract

Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal–regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity.