Jump to main content
Jump to site search

Issue 10, 2013
Previous Article Next Article

Bistability in a model of early B cell receptor activation and its role in tonic signaling and system tunability

Author affiliations

Abstract

Activation of the antigen receptors on the surface of B cells in response to their cognate ligands is tightly controlled by feedback mechanisms. Apart from ligand induced signaling, B cell receptors (BCRs) emanate ligand independent tonic signaling crucial for B cell survival and development. In the absence of a ligand, BCR tonic signaling is controlled by the basal activity of the Src family protein tyrosine kinase Lyn and the protein tyrosine phosphatase SHP. The binding of an antigen to the BCR causes receptor clustering or aggregation which is one of the earliest events in B cell activation. Lyn binds to aggregated receptors and phosphorylates them. In turn phosphorylation enhances the stability of receptor clusters against dissociation into monomers as well as the binding of Lyn to the receptor clusters, thereby producing positive feedback loops that enhance receptor clustering and activation. Apart from Lyn mediated positive feedback loops, SHP and BCR aggregates mutually inhibit each other to form a double negative feedback loop. Here, we present a simple computational model of BCR proximal signaling that incorporates these multiple feedback loops between the three molecules BCR, Lyn and SHP and their complexes. The model predicts bistable behaviour in the system that explains both the tonic signaling and ligand mediated receptor activation and a range of other biological phenomena in a unified manner. We find the bistability to be highly tunable by changes in the protein levels while remaining sufficiently robust to changes in the rate constants. The nested architecture of multiple feedback loops enhances the robustness of the bistability. Our model explains the recent experimental observation of the lack of response of germinal center B cells to ligand stimulation in terms of the tunability of the bistable switch by modification of SHP levels.

Graphical abstract: Bistability in a model of early B cell receptor activation and its role in tonic signaling and system tunability

Back to tab navigation

Supplementary files

Publication details

The article was received on 13 Mar 2013, accepted on 02 Jul 2013 and first published on 05 Jul 2013


Article type: Paper
DOI: 10.1039/C3MB70099B
Citation: Mol. BioSyst., 2013,9, 2498-2511
  •   Request permissions

    Bistability in a model of early B cell receptor activation and its role in tonic signaling and system tunability

    S. Ravichandran, K. V. S. Rao and S. Jain, Mol. BioSyst., 2013, 9, 2498
    DOI: 10.1039/C3MB70099B

Search articles by author

Spotlight

Advertisements