Hatzoglou A, Roussel J, Bourgeade MF, Rogier E, Madry C, Inoue J et al.. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol 165: 1322-1330

Laboratory of Experimental Endocrinology, Faculty of Medicine, University of Crete, Heraklion, Greece.
The Journal of Immunology (Impact Factor: 4.92). 09/2000; 165(3):1322-30. DOI: 10.4049/jimmunol.165.3.1322
Source: PubMed


BCMA (B cell maturation) is a nonglycosylated integral membrane type I protein that is preferentially expressed in mature B lymphocytes. Previously, we reported in a human malignant myeloma cell line that BCMA is not primarily present on the cell surface but lies in a perinuclear structure that partially overlaps the Golgi apparatus. We now show that in transiently or stably transfected cells, BCMA is located on the cell surface, as well as in a perinulear Golgi-like structure. We also show that overexpression of BCMA in 293 cells activates NF-kappa B, Elk-1, the c-Jun N-terminal kinase, and the p38 mitogen-activated protein kinase. Coimmunoprecipitation experiments performed in transfected cells showed that BCMA associates with TNFR-associated factor (TRAF) 1, TRAF2, and TRAF3 adaptor proteins. Analysis of deletion mutants of the intracytoplasmic tail of BCMA showed that the 25-aa protein segment, from position 119 to 143, conserved between mouse and human BCMA, is essential for its association with the TRAFs and the activation of NF-kappa B, Elk-1, and c-Jun N-terminal kinase. BCMA belongs structurally to the TNFR family. Its unique TNFR motif corresponds to a variant motif present in the fourth repeat of the TNFRI molecule. This study confirms that BCMA is a functional member of the TNFR superfamily. Furthermore, as BCMA is lacking a "death domain" and its overexpression activates NF-kappa B and c-Jun N-terminal kinase, we can reasonably hypothesize that upon binding of its corresponding ligand BCMA transduces signals for cell survival and proliferation.

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    • "These findings are consistent with the requirement for TACI for IgG production by B-cell cultures derived from Taci-knockout mice [65] [66] [67]. In that splenic B-cell culture system, APRIL or BAFF cooperates with Toll-like receptor- 9 agonists to induce B-cell differentiation, which is blocked by a neutralizing Ab against TACI [35] "
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    ABSTRACT: Long-lived plasma cells (PCs) contribute to humoral immunity through an undefined mechanism. Memory B cells, but not human naïve B cells, can be induced to differentiate into long-lived PCs in vitro. Because evidence links a proliferation-inducing ligand (APRIL), a tumor necrosis factor family member, to the ability of bone marrow to mediate long-term PC survival, we reasoned that APRIL influences the proliferation and differentiation of naïve B cells. We describe here the development of a simple cell culture system that allowed us to show that APRIL sustained the proliferation of naïve human B cells and induced them to differentiate into long-lived PCs. Blocking the transmembrane activator and calcium modulator and cyclophilin ligand interactor or B-cell mature antigen shows they were required for the differentiation of naïve B cells into long-lived PCs in vitro. Our in vitro culture system will reveal new insights into the biology of long-lived PCs. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cellular Immunology 03/2015; 111(2). DOI:10.1016/j.cellimm.2015.02.011 · 1.92 Impact Factor
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    • "Our demonstration that expression of a constitutively active mutant of GSK-3β prevents the axon growthpromoting action of APRIL suggests that this depends on GSK-3β inactivation. APRIL and BCMA are potent activators of NF-κB family of transcription factors (Hatzoglou et al., 2000; Kern et al., 2004). NF-κB signaling either promotes or inhibits neurite growth depending on the mechanism of NF-κB activation and phosphorylation status of the p65 NF-κB subunit (Gutierrez and Davies, 2011). "
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    ABSTRACT: APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation and has been implicated in tumorigenesis and autoimmune diseases. Here we report the expression and first known activity of APRIL in the nervous system. APRIL and one of its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells of fetal and postnatal mice. In culture, these neurons secreted APRIL, and function-blocking antibodies to either APRIL or BCMA reduced axonal elongation. Recombinant APRIL enhanced axonal elongation, but did not influence dendrite elongation. The effect of APRIL on axon elongation was inhibited by anti-BCMA and the expression of a signalling-defective BCMA mutant in these neurons, suggesting that the axon growth-promoting effect of APRIL is mediated by BCMA. APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3β in cultured hippocampal pyramidal cells. Inhibition of MEK1/MEK2 (activators of ERK1/ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth-promoting action of APRIL, as did pharmacological activation of GSK-3β and the expression of a constitutively active form of GSK-3β. These findings suggest that APRIL promotes axon elongation by a mechanism that depends both on ERK signaling and PI3-kinase/Akt/GSK-3β signaling.
    Molecular and Cellular Neuroscience 01/2014; 59(100). DOI:10.1016/j.mcn.2014.01.002 · 3.84 Impact Factor
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    • "TACI is able to recruit TRAFs 2, 5, and 6 to its cytoplasmic domain (29) and has been shown to activate NF-κB1, AP-1, and NFAT signaling pathways (30). BCMA has binding sites for TRAFs 1, 2, and 3 in its cytoplasmic tail and is capable of activating NF-κB1, Elk-1, p38 MAPK, and JNK signaling pathways (31). BAFFR contains only a single TRAF binding site, specific for TRAF3 and efficiently activates the NF-κB2 signaling pathway (32). "
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    ABSTRACT: It has been more than a decade since it was recognized that the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) transcription factor family was activated by two distinct pathways: the canonical pathway involving NF-κB1 and the non-canonical pathway involving NF-κB2. During this time a great deal of evidence has been amassed on the ligands and receptors that activate these pathways, the cytoplasmic adapter molecules involved in transducing the signals from receptors to nucleus, and the resulting physiological outcomes within body tissues. In contrast to NF-κB1 signaling, which can be activated by a wide variety of receptors, the NF-κB2 pathway is typically only activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor (TNF) family. Amongst these is B cell activating factor of the TNF family (BAFF) and its receptor BAFFR. Whilst BAFF is produced by many cell types throughout the body, BAFFR expression appears to be restricted to the hematopoietic lineage and B cells in particular. For this reason, the main physiological outcomes of BAFF mediated NF-κB2 activation are confined to B cells. Indeed BAFF mediated NF-κB2 signaling contributes to peripheral B cell survival and maturation as well as playing a role in antibody responses and long term maintenance plasma cells. Thus the importance BAFF and NF-κB2 permeates the entire B cell lifespan and impacts on this important component of the immune system in a variety of ways.
    Frontiers in Immunology 01/2014; 4:509. DOI:10.3389/fimmu.2013.00509
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