Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading

Abstract

In the context of cell signaling, kinetic proofreading was introduced to explain how cells can discriminate among ligands based on a kinetic parameter, the ligand-receptor dissociation rate constant. In the kinetic proofreading model of cell signaling, responses occur only when a bound receptor undergoes a complete series of modifications. If the ligand dissociates prematurely, the receptor returns to its basal state and signaling is frustrated. We extend the model to deal with systems where aggregation of receptors is essential to signal transduction, and present a version of the model for systems where signaling depends on an extrinsic kinase. We also investigate the kinetics of signaling molecules, ''messengers,'' that are generated by aggregated receptors but do not remain associated with the receptor complex. We show that the extended model predicts modes of signaling that exhibit kinetic discrimination for some range of parameters but for other parameter values show little or no discrimination and thus escape kinetic proofreading. We compare model predictions with experimental data.A n important feature of receptor-mediated cell signaling pathways is the capacity to discriminate between different ligands that bind to the same receptor. McKeithan introduced a kinetic proofreading model to explain such discrimination in T cell activation (1). In the model, the bound receptor must complete a series of modifications (e.g., phosphorylations, associations with kinases, phosphatases, adapter molecules) for a particular cellular response to occur. If the ligand dissociates before the full set of modifications is completed, the receptor reverts to its basal state. The model explains in part the correlation between the ability of peptide-MHC to activate T cells and the lifetime of the bond formed between the clonotypic T cell antigen receptor (TCR) and the peptide-MHC (2). In kinetic proofreading, cells discriminate between ligands based on a kinetic parameter, the dissociation rate constant, rather than on the equilibrium binding properties of the ligands.Recent experiments (3, 4) investigated the extent to which kinetic proofreading controls cellular responses induced by FcRI, a receptor homologous to TCR and other multichain immune recognition receptors (MIRR; ref. 5), which binds IgE with high affinity. Multivalent antigen, binding to the IgE, aggregates the FcRI and initiates cellular responses (6, 7). The experiments in ref. 3 showed that certain cellular responses induced by FcRI were consistent, qualitatively, with predictions of McKeithan's kinetic proofreading model (1). In the accompanying paper (4), newer studies support and extend the earlier ones, but also reveal a response that escapes kinetic proofreading, in the sense that ligands with widely different dissociation rate constants induce the same level of response. The authors propose an escape route-a branch from the chain of modifications of aggregated receptors, corresponding to a reaction in which a modified aggregate generates a ''messenger'' th...

Unexpected signals in a system subject to kinetic proofreading

“…Possibly, the anomalous results reflect an inactivation of phosphorylated Syk (25). However, the model described in the accompanying paper does not predict the results if such a step is introduced (26). Likewise, the data are not explained by postulating that some of the phosphorylated Syk dissociates from the aggregated receptors but remains phosphorylated for a time consistent with results from experiments in which receptors were disaggregated with hapten (26).…”

“…However, the model described in the accompanying paper does not predict the results if such a step is introduced (26). Likewise, the data are not explained by postulating that some of the phosphorylated Syk dissociates from the aggregated receptors but remains phosphorylated for a time consistent with results from experiments in which receptors were disaggregated with hapten (26). Similarly, neither the basic nor modified models predict the delay in the maximum phosphorylation of Syk achieved by the low-affinity ligand (Fig.…”

“…The accompanying paper (26) presents a formal analysis of such a branch in a pathway that is otherwise under kinetic proofreading control (figure 5a in ref. 26).…”

Signaling cascades: Escape from kinetic proofreading

“…These results suggested that not all responses to signaling cascades, which otherwise seemed to involve kinetic proofreading, followed the expected traits of such a system. In the theoretical treatment of this model system explored by Hlavacek et al (2), the authors provide insights into how it is possible to have discordant results like this in a system that nevertheless has properties consistent with kinetic proofreading. The authors offer several possible routes for responses to escape the intrinsic kinetic proofreading of the initial signaling events.…”

“…One general formulation of the reaction cascade has been termed kinetic proofreading. Two papers in this issue of PNAS, Liu et al (1) and Hlavacek et al (2), examine the characteristics of a reaction in rat basophilic leukemia cells, which have been shown previously to have behavior consistent with a kinetic proofreading scheme. The experimental study by Lui et al presents evidence for a response in these cells that does not follow the kinetic proofreading scheme, whereas the second paper explores the theoretical underpinnings that allow a response to escape from kinetic proofreading.…”