A Computational Model for Early Events in B Cell Antigen Receptor Signaling: Analysis of the Roles of Lyn and Fyn

Abstract

BCR signaling regulates the activities and fates of B cells. BCR signaling encompasses two feedback loops emanating from Lyn and Fyn, which are Src family protein tyrosine kinases (SFKs). Positive feedback arises from SFK-mediated trans phosphorylation of BCR and receptor-bound Lyn and Fyn, which increases the kinase activities of Lyn and Fyn. Negative feedback arises from SFK-mediated cis phosphorylation of the transmembrane adapter protein PAG1, which recruits the cytosolic protein tyrosine kinase Csk to the plasma membrane, where it acts to decrease the kinase activities of Lyn and Fyn. To study the effects of the positive and negative feedback loops on the dynamical stability of BCR signaling and the relative contributions of Lyn and Fyn to BCR signaling, we consider in this study a rule-based model for early events in BCR signaling that encompasses membrane-proximal interactions of six proteins, as follows: BCR, Lyn, Fyn, Csk, PAG1, and Syk, a cytosolic protein tyrosine kinase that is activated as a result of SFK-mediated phosphorylation of BCR. The model is consistent with known effects of Lyn and Fyn deletions. We find that BCR signaling can generate a single pulse or oscillations of Syk activation depending on the strength of Ag signal and the relative levels of Lyn and Fyn. We also show that bistability can arise in Lyn- or Csk-deficient cells.

Department(s)

Chemical and Biochemical Engineering

Keywords and Phrases

B Lymphocyte Antigen; Breakpoint Cluster Region Protein; Cytosolic Protein Tyrosine Kinase; Protein Kinase Fyn; Protein Kinase Lyn; Protein Kinase Syk; Protein PAG1; Protein Tyrosine Kinase; Unclassified Drug, Analytic Method; Article; Autophosphorylation; Bifurcation Parameter; Controlled Study; Negative Feedback; Priority Journal; Protein Binding; Protein Expression; Protein Function; Protein Phosphorylation; Sensitivity Analysis; Simulation, Animals; Calcium Signaling; Computer Simulation; Feedback, Physiological; Humans; Models, Immunological; Proto-Oncogene Proteins C-Fyn; Receptors, Antigen, B-Cell; Signal Transduction; Src-Family Kinases

International Standard Serial Number (ISSN)

0022-1767

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2012 American Association of Immunologists, Inc., All rights reserved.

Publication Date

01 Jul 2012

PubMed ID

22711887

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