On the origin of bistability in the Stage 2 of the Huang-Ferrell model of the MAPK signaling

Abstract

Mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes, unique to eukaryotes, that are involved in many pathways of cellular regulation. Successive phosphorylation cascades mediated by MAPKs serve as sensitive switches initiating various cellular processes. Apart from this basic feature, the underlying reaction network is capable of displaying other nonlinear phenomena including bistable steady states and hysteresis as well as periodic oscillations. We show that from the mechanistic point of view, bistability is a consequence of interaction between single and double phosphorylation/dephosphorylation pathways in a Stage 2 subsystem of the Huang-Ferrell model. Within this subsystem we uncover the core subnetwork obtained by systematic reduction relying on the methods of stoichiometric network analysis. For the core model we show that there is either one stable steady state or three steady states of which two are stable and point out the role of interplay between the single and double phosphorylation subnetworks in generating bistability.