ArticleScience signaling2014
The autoinhibitory C-terminal SH2 domain of phospholipase C-γ2 stabilizes B cell receptor signalosome assembly.
Article in Science signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 37 citations in OpenAlex.
- The role of MiRNA-mediated tumor microenvironment in bone metastasis from a multi-omics perspective: cross-cancer mechanisms and clinical translation.Frontiers in oncology · 2026Review
- Single-cell profiling uncovers the intricate pathological niche diversity in brain, lymph node, bone, and adrenal metastases of lung cancer.Discover oncology · 2025Article
- SIV-specific neutralizing antibody induction following selection of a PI3K drive-attenuatedeLife · 2025Article
- Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency.The Journal of allergy and clinical immunology · 2024Article
- PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants.The Journal of allergy and clinical immunology · 2024Article
- B cell receptor ligation induces IgE plasma cell elimination.The Journal of experimental medicine · 2023Article
- PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer's disease.Frontiers in cell and developmental biology · 2022Review
- PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.The EMBO journal · 2021Article
- BCALM (AC099524.1) Is a Human B Lymphocyte-Specific Long Noncoding RNA That Modulates B Cell Receptor-Mediated Calcium Signaling.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations.eLife · 2019Article
- The regulators of BCR signaling during B cell activation.Blood science (Baltimore, Md.) · 2019Review
- Article
- [Structure and function of B-cell linker and its role in the development of B cell-related diseases].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2019Article
- Intrinsic properties of human germinal center B cells set antigen affinity thresholds.Science immunology · 2018Article
- Toll-like receptor 9 antagonizes antibody affinity maturation.Nature immunology · 2018Article
- PLAID: a Syndrome of Complex Patterns of Disease and Unique Phenotypes.Journal of clinical immunology · 2015Review
- Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind.Current opinion in immunology · 2015Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The binding of antigen to the B cell receptor (BCR) stimulates the assembly of a signaling complex (signalosome) composed initially of the kinases Lyn, spleen tyrosine kinase (Syk), and Bruton's tyrosine kinase (Btk), as well as the adaptor protein B cell linker (BLNK). Together, these proteins recruit and activate phospholipase C-γ2 (PLC-γ2), a critical effector that stimulates increases in intracellular Ca(2+) and activates various signaling pathways downstream of the BCR. Individuals with one copy of a mutant PLCG2 gene, which encodes a variant PLC-γ2 that lacks the autoinhibitory C-terminal Src homology 2 (cSH2) domain, exhibit PLC-γ2-associated antibody deficiency and immune dysregulation (PLAID). Paradoxically, although COS-7 cells expressing the variant PLC-γ2 show enhanced basal and stimulated PLC-γ2 activity, B cells from PLAID patients show defective intracellular Ca(2+) responses upon cross-linking of the BCR. We found that the cSH2 domain of PLC-γ2 played a critical role in stabilizing the early signaling complex that is stimulated by BCR cross-linking. In the presence of the variant PLC-γ2, Syk, Btk, and BLNK were only weakly phosphorylated and failed to stably associate with the BCR. Thus, BCRs could not form stable clusters, resulting in dysregulation of downstream signaling and trafficking of the BCR. Thus, the cSH2 domain functions not only to inhibit the active site of PLC-γ2 but also to directly or indirectly stabilize the early BCR signaling complex.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.