title: Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.
abstract: The Src and Syk families of kinases are two distinct sets of kinases that play critical roles in initiating membrane-proximal B cell receptor (BCR) signaling. However, unlike in other lymphocytes, such as T cells, the "division of labor" between Src family kinases (SFKs) and Syk in B cells is not well separated because both Syk and SFKs can phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) present in proteins comprising the BCR. To understand why B cells require both SFKs and Syk for activation, we investigated the roles of both families of kinases in BCR signaling with computational modeling and in vitro experiments. Our computational model suggested that positive feedback enabled Syk to substantially compensate for the absence of SFKs when spatial clustering of BCRs was induced by multimeric ligands. We confirmed this prediction experimentally. In contrast, when B cells were stimulated by monomeric ligands that failed to produce BCR clustering, both Syk and SFKs were required for complete and rapid BCR activation. Our data suggest that SFKs could play a pivotal role in increasing BCR sensitivity to monomeric antigens of pathogens and in mediating a rapid response to soluble multimeric antigens of pathogens that can induce spatial BCR clustering.
authors.affiliation: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
authors.forename: Sayak
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.forename: Julie
authors.initials: J
authors.lastname: Zikherman
authors.forename: Ramya
authors.initials: R
authors.lastname: Parameswaran
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kadlecek
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Byron
authors.initials: B
authors.lastname: Au-Yeung
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: Jayajit
authors.initials: J
authors.lastname: Das
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D003001:Cloning, Molecular; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D009010:Monte Carlo Method; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D061987:Sf9 Cells; D015398:Signal Transduction / Q000276:immunology*; D018411:Spodoptera; D000072377:Syk Kinase; D014461:Ultracentrifugation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human