Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases
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Ploegh_Monovalent and multivalent.pdf
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Author(s)
Mukherjee, Sayak
Zhu, Jing
Zikherman, Julie
Parameswaran, Ramya
Kadlecek, Theresa A.
Wang, Qi
Au-Yeung, Byron
Ploegh, Hidde
Kuriyan, John
Das, Jayajit
Date Issued
January 2013
Journal
Science Signaling
Publisher
American Association for the Advancement of Science
Citation
Mukherjee, S., J. Zhu, J. Zikherman, R. Parameswaran, T. A. Kadlecek, Q. Wang, B. Au-Yeung, et al. “Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases.” Science Signaling 6, no. 256 (January 1, 2013): ra1-ra1.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1126/scisignal.2003220
