Document Detail


Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.
MedLine Citation:
PMID:  23281368     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Sayak Mukherjee; Jing Zhu; Julie Zikherman; Ramya Parameswaran; Theresa A Kadlecek; Qi Wang; Byron Au-Yeung; Hidde Ploegh; John Kuriyan; Jayajit Das; Arthur Weiss
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-01
Journal Detail:
Title:  Science signaling     Volume:  6     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-06-05     Revised Date:  2014-04-29    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  ra1     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal
B-Lymphocytes / immunology*,  metabolism,  physiology
Cloning, Molecular
Computer Simulation
Feedback, Physiological / physiology*
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics,  metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Immunological*
Monte Carlo Method
Phosphorylation
Protein-Tyrosine Kinases / genetics,  metabolism*
Receptors, Antigen, B-Cell / metabolism*
Sf9 Cells
Signal Transduction / immunology*
Spodoptera
Ultracentrifugation
ZAP-70 Protein-Tyrosine Kinase / metabolism
src-Family Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
AI090115/AI/NIAID NIH HHS; K08 AR059723/AR/NIAMS NIH HHS; KO8 AR059723/AR/NIAMS NIH HHS; P01 AI091580/AI/NIAID NIH HHS; P01 AI091580/AI/NIAID NIH HHS; P30 DK063720/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Intracellular Signaling Peptides and Proteins; 0/Receptors, Antigen, B-Cell; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Syk kinase; EC 2.7.10.2/CSK tyrosine-protein kinase; EC 2.7.10.2/ZAP-70 Protein-Tyrosine Kinase; EC 2.7.10.2/src-Family Kinases
Comments/Corrections
Comment In:
Sci Signal. 2013 May 7;6(274):jc2   [PMID:  23652201 ]

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