%0 Journal Article
%T Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation
%A Barbara Szomolay
%A Vahid Shahrezaei
%J BMC Systems Biology
%D 2012
%I BioMed Central
%R 10.1186/1752-0509-6-26
%X We first revisit the basic PDC and show that partial asymptotic phosphorylation of substrate limits ultrasensitivity. Also, substrate levels are changed one can obtain non-monotonic bell-shaped dose-response curves over a narrow range of parameters. Then we extend the PDC to include kinase-phosphatase complex formation. We report the possibility of robust bell-shaped dose-response for a specific class of the model with complex formation. Also, we show that complex formation can produce ultrasensitivity outside the Goldbeter-Koshland zero-order ultrasensitivity regime through a mechanism similar to competitive inhibition between an enzyme and its inhibitor.We conclude that the novel PDC module studied here exhibits new dose-response behaviour. In particular, we show that the bell-shaped response could result in transient phosphorylation of substrate. We discuss the relevance of this result in the context of experimental observations on PI regulation in endosomal trafficking.Biochemical networks have a modular structure [1]. The functional modules have different dynamical and input-output properties [2,3]. For example positive feedback loops can produce bistability while negative feedback loops filter noise. An important biochemical module in cellular signalling is a phosphorylation-dephosphorylation cycle (PDC). Phosphorylation is a common post-translational covalent modification of proteins and lipids, that is mediated by kinases and needs ATP to proceed. However, dephosphorylation is mediated by phosphatases and does not need ATP to proceed. Phosphorylation can affect binding properties, localization and activity of proteins and receptors [4].Systems with phosphorylation-dephosphorylation cycles can exhibit a variety of input-output or dose-response behaviors [5]. The level of phosphorylated substrate at steady-state is controlled by the kinase-phosphatase balance (KPB), i.e., the ratio of total active kinase to active phosphatase concentration. If the enzymes are
%K Cellular signalling
%K Zero-order ultrasensitivity
%K Phosphoinositide regulation
%K Endosomal trafficking
%U http://www.biomedcentral.com/1752-0509/6/26