February 25, Mon 2013
11:00 am, MRB 100C
Dr. Dipak Barua
Center for Nonlinear Studies, Los Alamos National Laboratory
Investigation of the roles of Src family tyrosine kinases in immune response signaling and their redundancy: focus on B cell receptor signaling
Signaling responses in T-cells, B-cells, and mast cells are activated by Src family protein tyrosine kinases (SFKs) following aggregation of cell-surface receptors by antigens. The SFKs, having highly homologous structures, mediate similar interactions with other signaling proteins in the signaling pathways. In this study, we investigate the roles of two SFKs, Lyn and Fyn, which activate B cell antigen receptor (BCR) signaling. BCR signaling encompasses two feedback loops emanating from Lyn and Fyn. 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.