Cutting Edge: Feed-Forward Activation of Phospholipase Cγ2 via C2 Domain–Mediated Binding to SLP65
Abstract
Ag-mediated B cell stimulation relies on phospholipase Cγ2 (PLCγ2) for Ca(2+) mobilization. Enzymatic activity of PLCγ2 is triggered upon Src homology 2 domain-mediated binding to the tyrosine-phosphorylated adaptor SLP65. However, SLP65 phosphorylation outlasts the elevation of cytosolic Ca(2+) concentration suggesting additional levels of PLCγ2 regulation. We show in this article that the functionality of the PLCγ2/SLP65 complex is controlled by the weakly characterized C2 domain of PLCγ2. Usually C2 domains bind membrane lipids, but that of PLCγ2 docks in a Ca(2+)-regulated manner to a distinct phosphotyrosine of SLP65. Hence, early Ca(2+) fluxing provides feed-forward signal amplification by promoting anchoring of the PLCγ2 C2 domain to phospho-SLP65. As the cellular Ca(2+) resources become exhausted, the concomitant decline of Ca(2+) dampens the C2-phosphotyrosine interaction so that PLCγ2 activation terminates despite sustained SLP65 phosphorylation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Binding of the SH2 domain to BLNK is stabilized by the C2 domain in a calcium-regulated manner.
“As a consequence, binding of the SH2 domain to BLNK is also stabilized by the C2 domain in a calcium-regulated manner (44).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [44]
The C2 domain of PLCγ2, in which the APLAID mutation M1141L resides, is critical for calcium-dependent translocation of PLCγ2 to the plasma membrane for sustained influx of extracellular calcium.
“The C2 domain of PLCγ2, in which the APLAID mutation M1141L resides, has previously been shown to be critical for calcium-dependent translocation of PLCγ2 to the plasma membrane for the sustained influx of extracellular calcium.”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [44]
Cites
Fu (1998) · doi:10.1016/s1074-7613(00)80591-9 · Cited by 518 · see citing works
Recognition and specificity in protein tyrosine kinase-mediated signalling
Songyang, Z., & Cantley, L. C. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89103-3 · Cited by 370 · see citing works
SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond
Koretzky, G. A., Abtahian, F., & Silverman, M. A. (2006) · Nature reviews. Immunology · doi:10.1038/nri1750 · Cited by 278 · see citing works
Wienands, J., Schweikert, J., Wollscheid, B., Jumaa, H., Nielsen, P. J., & Reth, M. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.4.791 · Cited by 271 · see citing works
Self-citationThe C2 Domain of PKCδ Is a Phosphotyrosine Binding Domain
Benes, C. H., Wu, N., Elia, A. E. H., Dharia, T., Cantley, L. C., & Soltoff, S. P. (2005) · Cell · doi:10.1016/j.cell.2005.02.019 · Cited by 246 · see citing works
Hashimoto, S., Iwamatsu, A., Ishiai, M., Okawa, K., Yamadori, T., Matsushita, M., Baba, Y., Kishimoto, T., Kurosaki, T., & Tsukada, S. (1999) · Blood · doi:10.1182/blood.v94.7.2357.419k40_2357_2364 · Cited by 206 · see citing works
BLNK: molecular scaffolding through ‘cis’‐mediated organization of signaling proteins
Chiu, C. W., Dalton, M., Ishiai, M., Kurosaki, T., & Chan, A. C. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf658 · Cited by 122 · see citing works
Nishida, M., Sugimoto, K., Hara, Y., Mori, E., Morii, T., Kurosaki, T., & Mori, Y. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg457 · Cited by 110 · see citing works
Potsch, C., Voehringer, D., & Pircher, H. (1999) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199911)29:11 · Cited by 92 · see citing works
Self-citationC2 domain conformational changes in phospholipase C-δ1
Grobler, J., Essen, L., Williams, R. L., & Hurley, J. (1996) · Nature Structural Biology · doi:10.1038/nsb0996-788 · Cited by 87 · see citing works
The B‐cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85
Oellerich, T., Bremes, V., Neumann, K., Bohnenberger, H., Dittmann, K., Hsiao, H., Engelke, M., Schnyder, T., Batista, F. D., Urlaub, H., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.251 · Cited by 85 · see citing works
Self-citationCa2+ signaling in antigen receptor‐activated B lymphocytes
Engelke, M., Engels, N., Dittmann, K., Stork, B., & Wienands, J. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00539.x · Cited by 80 · see citing works
Self-citationOellerich, T., Grønborg, M., Neumann, K., Hsiao, H., Urlaub, H., & Wienands, J. (2009) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800567-mcp200 · Cited by 43 · see citing works
Self-citationSequential phosphorylation of SLP‐76 at tyrosine 173 is required for activation of T and mast cells
Sela, M., Bogin, Y., Beach, D., Oellerich, T., Lehne, J., Smith‐Garvin, J. E., Okumura, M., Starosvetsky, E., Kosoff, R. E., Libman, E., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.213 · Cited by 37 · see citing works
Self-citationStahelin, R. V., Kong, K., Raha, S., Tian, W., Melowic, H. R., Ward, K. E., Murray, D., Altman, A., & Cho, W. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.391557 · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration
Jackson, J. T., Mulazzani, E., Nutt, S. L., & Masters, S. L. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100905 · Cited by 113 · see citing works
“As a consequence, binding of the SH2 domain to BLNK is also stabilized by the C2 domain in a calcium-regulated manner (44).”
BackgroundNovice, T., Kariminia, A., Del Bel, K. L., Lu, H., Sharma, M., Lim, C. J., Read, J., Lugt, M. V., Hannibal, M. C., O’Dwyer, D., et al. (2020) · Journal of Clinical Immunology · doi:10.1007/s10875-019-00731-3 · Cited by 44 · see citing works
Wang, J., Sohn, H., Sun, G., Milner, J. D., & Pierce, S. K. (2014) · Science Signaling · doi:10.1126/scisignal.2005392 · Cited by 36 · see citing works
The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells
Krishnamoorthy, M., Wasim, L., Buhari, F. H. M., Zhao, T., Mahtani, T., Ho, J., Kang, S., Deason-Towne, F., Perraud, A., Schmitz, C., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aah6692 · Cited by 33 · see citing works
G-CSF drives autoinflammation in APLAID
Mulazzani, E., Kong, K., Aróstegui, J. I., Ng, A. P., Ranathunga, N., Abeysekera, W., Garnham, A. L., Ng, S., Baker, P. J., Jackson, J. T., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01473-6 · Cited by 24 · see citing works
Scaffold Protein SLP-76 Primes PLCγ1 for Activation by ITK-Mediated Phosphorylation
Devkota, S., Joseph, R. E., Min, L., Fulton, D. B., & Andreotti, A. H. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.04.012 · Cited by 22 · see citing works
Budzyńska, P. M., Niemelä, M., Sarapulov, A. V., Kyläniemi, M. K., Nera, K. ‐., Junttila, S., Laiho, A., Mattila, P. K., Alinikula, J., & Lassila, O. (2015) · Scandinavian Journal of Immunology · doi:10.1111/sji.12343 · Cited by 7 · see citing works
Weis, V., Königsberger, S., Amler, S., Wienands, J., & Kiefer, F. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00216-17 · Cited by 1 · see citing works
Self-citationAdapter Molecules in Immune Receptor Signaling
Jordan, M. S., & Koretzky, G. A. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-374279-7.11003-3
Scaffold and Adapter Molecules in Immune Receptor Signaling
Snow, A. L. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00160-5
- Authors
- Engelke, M., Oellerich, T., Dittmann, K., Hsiao, H.-H., Urlaub, H., Serve, H., Griesinger, C., & Wienands, J.
- Affiliations
- University of Göttingen (DE)
- Goethe University Frankfurt (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Engelke, Michael
- Oellerich, Thomas
- Dittmann, Kai
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-12-01
- Volume
- 191
- Issue
- 11
- Pages
- 5354-5358
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2127036750
- Cited by
- 10
- References
- 15
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 1
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- PLCγ2, C2 domain, B cell activation, calcium mobilization, phosphotyrosine, signal termination, lipid membrane binding
- MeSH terms
- Animals, Antigens, B-Lymphocytes, Calcium, Cell Line, Chickens, Humans, Lymphocyte Activation, Mutation, Phosphorylation, Protein Binding, Protein Engineering, Protein Structure, Tertiary, Transgenes, Calcium Signaling, Amino Acid Motifs, Feedback, Physiological, Adaptor Proteins, Signal Transducing, Phospholipase C gamma
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
