Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases

Sayak Mukherjee, Jing Zhu, Julie Zikherman, Ramya Parameswaran, Theresa A. Kadlecek, Qi Wang, Byron Au-Yeung, Hidde Ploegh, John Kuriyan, Jayajit Das,* Arthur Weiss*

*To whom correspondence should be addressed. E-mail: aweiss{at}medicine.ucsf.edu (A.W.); das.70{at}osu.edu (J.D.)

This PDF file includes:

• Methods (sections 1 to 8)
• Fig. S1. Details of the simulation method.
• Fig. S2. Effect of clustering on ITAM phosphorylation when signaling is induced predominantly by dimers or higher-order multimers.
• Fig. S3. Snapshots of the dynamic clustering of antigen-bound BCRs and the kinetics of ITAM phosphorylation in the simulation.
• Fig. S4. The kinetics of ITAM phosphorylation in the context of SFK-mediated phosphorylation of Syk.
• Fig. S5. The coarse-graining scheme used in the model.
• Fig. S6. Quantification of serial receptor triggering.
• Fig. S7. Effect of low-affinity ligands on ITAM phosphorylation.
• Fig. S8. Basal phosphorylation.
• Fig. S9. Effect of Src-mediated transphosphorylation.
• Fig. S10. Bistability in the presence of both of the Syk-mediated feedback mechanisms.
• Fig. S11. The dose-response curve in Src knockout B cells in the absence of transphosphorylation of BCR-bound Syk.
• Fig. S12. Minimal model.
• Fig. S13. Sensitivity of the rate constants.
• Fig. S14. Sensitive rate constants I.
• Fig. S15. Sensitive rate constants II.
• Fig. S16. Sensitive rate constants III.
• Fig. S17. Sensitivity analysis of concentrations.
• Fig. S18. Sensitive concentration I.
• Fig. S19. Sensitive concentration II.
• Fig. S20. Sensitivity analysis for varying the amount of antigens present in the BCR microcluster.
• Fig. S21. Effect of increasing the number of Syk and SHP-1 molecules by two orders of magnitude.
• Fig. S22. Effect of varying the rates of Src kinase domain binding to unphosphorylated ITAMs.
• Table S1. Reactions and the rate constants used.
• Table S2. Concentrations of the signaling molecules used in the simulations.
• Table S3. Sensitivity analysis for variations of rate constants.
• Table S4. Sensitivity analysis for variations of concentrations of signaling molecules.
• Movies S1 to S3 legends
• References (61–66)
  

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Other Supplementary Material for this manuscript includes the following:

• Movie S1 (.mov format). The dynamics of antigen-bound BCRs in the tagged state (yellow dots).
• Movie S2 (.mov format). The kinetics of cluster formation by antigen-bound BCRs (green dots).
• Movie S3 (.mov format). The kinetics of ITAM phosphorylation when the antigen-bound BCRs form clusters dynamically in the absence of SFKs.

© 2013 American Association for the Advancement of Science