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Sci. Signal., 1 January 2013
Vol. 6, Issue 256, p. ra1
[DOI: 10.1126/scisignal.2003220]


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

Sayak Mukherjee1, Jing Zhu2, Julie Zikherman2, Ramya Parameswaran2, Theresa A. Kadlecek2, Qi Wang3, Byron Au-Yeung2, Hidde Ploegh4, John Kuriyan3, Jayajit Das1,5,6*, and Arthur Weiss2*

1 Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
2 The Rosalind Russell Research Center for Arthritis, Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
3 Department of Molecular and Cell Biology, Department of Chemistry, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
4 Department of Biology, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
5 Department of Physics, The Ohio State University, Columbus, OH 43210, USA.
6 Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA.

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.

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

Citation: S. Mukherjee, J. Zhu, J. Zikherman, R. Parameswaran, T. A. Kadlecek, Q. Wang, B. Au-Yeung, H. Ploegh, J. Kuriyan, J. Das, A. Weiss, Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases. Sci. Signal. 6, ra1 (2013).

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