Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases
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...
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| Language: | en_US |
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American Association for the Advancement of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/85100 https://orcid.org/0000-0002-1090-6071 |
| _version_ | 1826192909642235904 |
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| author | Mukherjee, Sayak Zhu, Jing Zikherman, Julie Parameswaran, Ramya Kadlecek, Theresa A. Wang, Qi Au-Yeung, Byron Ploegh, Hidde Kuriyan, John Das, Jayajit Weiss, Arthur |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Mukherjee, Sayak Zhu, Jing Zikherman, Julie Parameswaran, Ramya Kadlecek, Theresa A. Wang, Qi Au-Yeung, Byron Ploegh, Hidde Kuriyan, John Das, Jayajit Weiss, Arthur |
| author_sort | Mukherjee, Sayak |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:30:42Z |
| format | Article |
| id | mit-1721.1/85100 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:30:42Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | mit-1721.1/851002022-09-30T14:55:04Z Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases Mukherjee, Sayak Zhu, Jing Zikherman, Julie Parameswaran, Ramya Kadlecek, Theresa A. Wang, Qi Au-Yeung, Byron Ploegh, Hidde Kuriyan, John Das, Jayajit Weiss, Arthur Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Ploegh, Hidde 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. National Institutes of Health (U.S.) (grant KO8 AR059723) National Institutes of Health (U.S.) (grant PO1 AI091580) Cancer Research Institute (New York, N.Y.) Cancer Research Institute (New York, N.Y.) (Irvington Institute Postdoctoral Fellowship) Nationwide Children's Hospital (Research Institute) National Institutes of Health (U.S.) (NIH grant AI090115) 2014-02-26T19:10:09Z 2014-02-26T19:10:09Z 2013-01 2012-05 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/85100 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. https://orcid.org/0000-0002-1090-6071 en_US http://dx.doi.org/10.1126/scisignal.2003220 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science PMC |
| spellingShingle | Mukherjee, Sayak Zhu, Jing Zikherman, Julie Parameswaran, Ramya Kadlecek, Theresa A. Wang, Qi Au-Yeung, Byron Ploegh, Hidde Kuriyan, John Das, Jayajit Weiss, Arthur Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases |
| title | Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases |
| title_full | Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases |
| title_fullStr | Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases |
| title_full_unstemmed | Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases |
| title_short | Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases |
| title_sort | monovalent and multivalent ligation of the b cell receptor exhibit differential dependence upon syk and src family kinases |
| url | http://hdl.handle.net/1721.1/85100 https://orcid.org/0000-0002-1090-6071 |
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