Rac-mediated stimulation of phospholipase Cγ2 amplifies B cell receptor-induced calcium signaling
Open accessAbstract
The Rho GTPase Rac is crucially involved in controlling multiple B cell functions, including those regulated by the B cell receptor (BCR) through increased cytosolic Ca 2+ . The underlying molecular mechanisms and their relevance to the functions of intact B cells have thus far remained unknown. We have previously shown that the activity of phospholipase Cγ 2 (PLCγ 2 ), a key constituent of the BCR signalosome, is stimulated by activated Rac through direct protein-protein interaction. Here, we use a Rac-resistant mutant of PLCγ 2 to functionally reconstitute cultured PLCγ 2 -deficient DT40 B cells and to examine the effects of the Rac-PLCγ 2 interaction on BCR-mediated changes of intracellular Ca 2+ and regulation of Ca 2+ -regulated and nuclear-factor-of-activated-T-cell-regulated gene transcription at the level of single, intact B cells. The results show that the functional Rac-PLCγ 2 interaction causes marked increases in the following: (i) sensitivity of B cells to BCR ligation; (ii) BCR-mediated Ca 2+ release from intracellular stores; (iii) Ca 2+ entry from the extracellular compartment; and (iv) nuclear translocation of the Ca 2+ -regulated nuclear factor of activated T cells. Hence, Rac-mediated stimulation of PLCγ 2 activity serves to amplify B cell receptor-induced Ca 2+ signaling. Background: Phospholipase Cγ 2 (PLCγ 2 ) is stimulated by Rac GTPases through direct protein-protein interaction. Results: The Rac-PLCγ 2 interaction markedly enhances B cell-receptor-mediated Ca 2+ mobilization and nuclear translocation of the Ca 2+ -regulated transcription factor NFAT in B cells. Conclusion: Rac-mediated stimulation of PLCγ 2 activity amplifies B cell receptor-induced Ca 2+ signaling. Significance: A specific Rac-resistant PLCγ 2 variant is used to determine the physiological cell signaling relevance of a functional Rac-PLCγ 2 interaction in an appropriate cellular context.
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In B cells, activation of Rac is not limited to BCR activation but also occurs upon activation of BCR coreceptors such as CD19/CD21, integrins, and certain G-protein-coupled chemokine and Toll-like receptors.
“In B cells, activation of Rac is not limited to BCR activation, but also occurs upon activation of BCR coreceptors, such as CD19/CD21, integrins, as well as certain G-protein-coupled chemokine and Toll-like receptors (cf.discussion and references in Ref. 34).”
From The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein (2016) · cites this paper as [34]
The discussion (page unavailable in our copy) says that receptors for integrins, chemokines, and pathogen-derived ligands can activate Rac in B cells; it specifically discusses CXCR4/CXCR5 and TLR4. It discusses CD19/CD21 coreceptor signaling only as a possible setting for Rac–PLCγ2 activity, not as evidence that activation of CD19/CD21 activates Rac. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInteraction of PLCγ2 with Rac amplifies BCR-induced Ca2+ signaling by increasing sensitivity to BCR ligation, augmenting BCR-mediated Ca2+ release from intracellular stores, enhancing Ca2+ entry from the extracellular compartment, and facilitating nuclear translocation of the Ca2+-regulated nuclear factor of activated T cells.
“we have previously shown that interaction of PLC␥ 2 with Rac amplifies the BCR-induced Ca 2ϩ signaling by increasing the sensitivity of the cells to BCR ligation, augmenting the BCR-mediated Ca 2ϩ release from intracellular stores, enhancing the Ca 2ϩ entry from the extracellular compartment, and facilitating the nuclear translocation of the Ca 2ϩ -regulated nuclear factor of activated T cells (34”
Rac-mediated stimulation of PLCγ2 amplifies BCR-mediated Ca2+ signaling.
“Studies using a Rac-resistant mutant of PLC␥ 2 , F897Q, reconstituted into PLC␥ 2 -deficient DT40 B cells recently showed that Rac-mediated stimulation of PLC␥ 2 amplifies BCR-mediated Ca 2ϩ signaling (34).”
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Cites
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“Studies using DT40 cells showed that Rac2 could also stimulate PLCγ2 to enhance the BCR-induced calcium flux (19).”
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- Authors
- Walliser, C., Tron, K., Clauss, K., Gutman, O., Kobitski, A. Y., Retlich, M., Schade, A., Röcker, C., Henis, Y. I., Nienhaus, G. U., & Gierschik, P.
- Affiliations
- Universität Ulm (DE)
- Tel Aviv University (IL)
- Karlsruhe Institute of Technology (DE)
- Corresponding author
- Gierschik, Peter
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 290
- Issue
- 28
- Pages
- 17056-17072
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4498044
- OpenAlex
- W1996163488
- Cited by
- 21
- References
- 12
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 8 · 2019: 1 · 2018: 3 · 2016: 3
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- Rac GTPase, PLCγ2, B cell receptor signaling, calcium signaling, intracellular calcium release, calcium influx, NFAT nuclear translocation, protein-protein interaction, DT40 B cells
- MeSH terms
- Animals, B-Lymphocytes, Cell Line, Chickens, Humans, Models, Molecular, Protein Conformation, Receptors, Antigen, B-Cell, Recombinant Proteins, Mutagenesis, Site-Directed, Amino Acid Substitution, Calcium Signaling, rac GTP-Binding Proteins, Active Transport, Cell Nucleus, Avian Proteins, NFATC Transcription Factors, Mice, Phospholipase C gamma
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