Point mutations of 3BP2 identified in human‐inherited disease cherubism result in the loss of function

Miah, S. M. Shahjahan; Hatani, Tomoko; Qu, Xiujuan; Yamamura, Hirohei; Sada, Kiyonao

doi:10.1111/j.1365-2443.2004.00784.x

Cited by 50 publications

(56 citation statements)

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“…All mutations in cherubism are located in exon 9 between the central proline-rich region and C-terminal SH2 domain and affect 3 amino acids within a 6-amino-acid sequence. The mutation in cherubism affects only one of the two 3BP2 alleles, and overexpression of the mutant in RBL-2H3 cells inhibits FcεRI-induced mast cell activation (37). Thus, the mutant gene product may function as a dominant-negative or gain-of-function mutant, rather than exerting its effect due to haploinsufficiency.…”

Section: Discussionmentioning

confidence: 99%

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3BP2 Deficiency Impairs the Response of B Cells, but Not T Cells, to Antigen Receptor Ligation

Fuente¹,

Kumar²,

et al. 2006

Molecular and Cellular Biology

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The adapter protein 3BP2 is expressed in lymphocytes; binds to Syk/ZAP-70, Vav, and phospholipase C-␥ (PLC-␥); and is thought to be important for interleukin-2 gene transcription in T cells. To define the role of 3BP2 in lymphocyte development and function, we generated 3BP2-deficient mice. T-cell development, proliferation, cytokine secretion, and signaling in response to T-cell receptor (TCR) ligation were all normal in 3BP2 ؊/؊ mice. 3BP2 ؊/؊ mice had increased accumulation of pre-B cells in the bone marrow and a block in the progression of transitional B cells in the spleen from the T1 to the T2 stage, but normal numbers of mature B cells. B-cell proliferation, cell cycle progression, PLC-␥2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to B-cell receptor (BCR) ligation were all impaired. These results suggest that 3BP2 is important for BCR, but not for TCR signaling.3BP2 is a protein originally characterized as an Abl SH3-interacting protein (44). It consists of an N-terminal pleckstrin homology domain, a proline-rich central region, and a C-terminal SH2 domain. 3BP2 mRNA is expressed in hematopoietic tissues. 3BP2 protein is expressed in T cells, B cells, natural killer (NK) cells, monocytic cell lines, osteoclasts, and the rat basophilic leukemia cell line RBL-2H3 (11, 37). 3BP2 associates with 36). Association of 3BP2 with Syk was shown to require the SH2 domain of 3BP2 and the catalytic activity of Syk. The SH2 domain of 3BP2 has also been shown to bind to the adapter protein LAT in T cells and mast cells after T-cell receptor (TCR) and FcεRI ligation, respectively (11, 46). Phospholipase C-␥ (PLC-␥) and Vav were also identified as binding partners of 3BP2 (22). Other partners of 3BP2 include Grb2, Cbl, and Fyn (11,14,15).TCR stimulation induces a significant translocation of 3BP2 to the membrane and detergent-insoluble (cytoskeleton) fractions, suggesting a role for 3BP2 in TCR-mediated signal transduction (11). Transient overexpression of 3BP2 in Jurkat T cells induces transcriptional activation of the interleukin-2 (IL-2) gene promoter and its NF-AT and AP-1 elements and cooperates with TCR ligation and ionomycin in activating NF-AT/AP-1-driven transcription. Overexpression of 3BP2 resulted in calcineurin-dependent dephosphorylation of NF-ATc and stimulated AP-1 activity independently of NF-AT (11). The SH2 and PH domains of 3BP2, but not its proline-rich domain, are required for NF-AT activation. Furthermore, overexpression of the SH2 domain of 3BP2 inhibited TCRmediated NF-AT activation (11). Activation of NF-AT by 3BP2 in T cells required ZAP-70, because overexpression of 3BP2 in a ZAP-70-deficient Jurkat cell clone failed to activate NF-AT (11). Overexpression of 3BP2 enhances NK cell-mediated cytotoxicity (22). FcεRI ligation induces the phosphorylation of 3BP2 and its association with LAT in rat basophilic leukemia RBL-2H3 cells (46). Overexpression of the SH2 domain of 3BP2 in these cells suppresses FcεRI-induced signaling (46).Recent...

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Section: Discussionmentioning

confidence: 99%

“…3BP2 mRNA is expressed in hematopoietic tissues. 3BP2 protein is expressed in T cells, B cells, natural killer (NK) cells, monocytic cell lines, osteoclasts, and the rat basophilic leukemia cell line RBL-2H3 (11,37). 3BP2 associates with Syk and ZAP-70 (11,36).…”

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confidence: 99%

3BP2 Deficiency Impairs the Response of B Cells, but Not T Cells, to Antigen Receptor Ligation

Fuente¹,

Kumar²,

et al. 2006

Molecular and Cellular Biology

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“…Recombinant protein PAK1-PBD-GST, which binds specifically to the GTP-bound forms of Rac and Cdc42, was produced as described previously (24). In brief, cDNA of the Rac-and Cdc42-binding domain of human PAK1 (PAK1-PBD; amino acids 67-150) was cloned into expression vector pGEX4T-3 as a fusion protein with glutathione S-transferase (GST) and was expressed in Escherichia coli DH5␣ cells treated with isopropyl ␤-D-thiogalactopyranoside (Nacalai Tesque, Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

Effects of Peripheral Cannabinoid Receptor Ligands on Motility and Polarization in Neutrophil-like HL60 Cells and Human Neutrophils

Kurihara

Tohyama

Matsusaka

et al. 2006

Journal of Biological Chemistry

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The possible role of the peripheral cannabinoid receptor (CB2) in neutrophil migration was investigated by using human promyelocytic HL60 cells differentiated into neutrophil-like cells and human neutrophils isolated from whole blood. Cell surface expression of CB2 on HL60 cells, on neutrophil-like HL60 cells, and on human neutrophils was confirmed by flow cytometry. Upon stimulation with either of the CB2 ligands JWH015 and 2-arachidonoylglycerol (2-AG), neutrophil-like HL60 cells rapidly extended and retracted one or more pseudopods containing F-actin in different directions instead of developing front/rear polarity typically exhibited by migrating leukocytes. Activity of the Rho-GTPase RhoA decreased in response to CB2 stimulation, whereas Rac1, Rac2, and Cdc42 activity increased. Moreover, treatment of cells with RhoA-dependent protein kinase (p160-ROCK) inhibitor Y27632 yielded cytoskeletal organization similar to that of CB2-stimulated cells. In human neutrophils, neither JWH015 nor 2-AG induced motility or morphologic alterations. However, pretreatment of neutrophils with these ligands disrupted N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced front/rear polarization and migration and also substantially suppressed fMLP-induced RhoA activity. These results suggest that CB2 might play a role in regulating excessive inflammatory response by controlling RhoA activation, thereby suppressing neutrophil migration.The peripheral cannabinoid receptor (CB2) 2 was cloned in 1993 (1) after cloning of the central cannabinoid receptor (CB1) in 1990 (2). It has been suggested that the gene encoding CB2 is a protooncogene and that aberrant expression of CB2 in myeloid precursor cells results in the development of leukemia by blocking neutrophil differentiation (3, 4). CB2 is expressed predominantly in immune cells (5), and because of the diversity of immune cells, it is assumed that CB2 is involved in various activities in addition to inhibition of neutrophil differentiation (6 -9). Steffens et al. (10) recently reported that doses of ⌬ 9 -tetrahydrocannabinol (the most psychoactive component of marijuana) too low to have psychotropic effects inhibit the progression of atherosclerosis via immunomodulatory effects on lymphoid and myeloid cells. This report indicates that CB2 may be involved in a wide range of physiologic phenomena related to immunity and that some CB2 ligands may have application in the treatment of inflammatory disease. However, research into CB2 is still in its early stages. In particular, the involvement of only a few molecules, G␣ i /G␣ o protein, phosphatidylinositol 3-kinase (PI3K), and members of the mitogen-activated protein kinase and nuclear factor-B families, in the CB2 signaling pathways has been reported (6 -8, 11).Among the possible roles of CB2 in immunity is the induction of leukocyte migration to sites of infection and inflammation, an important step in the host defense against pathogenic microorganisms. CB2 is a seven-transmembrane, G␣ i /G␣ o protein-coupled receptor, as ar...

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“…Enfin, 3BP2 peut être phosphorylée sur des résidus sérine par la PKC, et se complexer avec les protéines 14-3-3 via les sérines 225 et 277 [13]. L'impact de ces phosphorylations sur la fonction de 3BP2 est inconnu, mais elles pourraient réguler négativement la signalisation par 3BP2 dans les cellules T et les mastocytes [13,14].…”

Section: Bp2 : Structure Et Partenaires Moléculairesunclassified

“…Cependant, la présence dans les os de la mâchoire d'un excès d'ostéoclastes multinucléés suggère que les protéines 3BP2 mutantes altèrent les voies de signalisation des ostéoclastes, des cellules essentielles à l'homéostasie osseuse et se différenciant à partir de progéniteurs myélomonocytaires de la moelle osseuse sous l'action du récepteur RANK, notamment, ainsi que d'autres signaux [25]. Il faut noter qu'une étude récente a montré que la surexpression de mutants « chérubisme » de 3BP2 dans la lignée basophile RBL-2H3 a un effet dominant négatif sur la signalisation du récepteur FcεRI [14]. Des altérations moléculaires analogues restent toutefois à démontrer dans les ostéoclastes ou les autres cellules régulant le remodelage osseux.…”

Section: Bp2 : Structure Et Partenaires Moléculairesunclassified

L’adaptateur 3BP2

Deckert

2006

Med Sci (Paris)

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Point mutations of 3BP2 identified in human‐inherited disease cherubism result in the loss of function

Cited by 50 publications

References 27 publications

3BP2 Deficiency Impairs the Response of B Cells, but Not T Cells, to Antigen Receptor Ligation

3BP2 Deficiency Impairs the Response of B Cells, but Not T Cells, to Antigen Receptor Ligation

Effects of Peripheral Cannabinoid Receptor Ligands on Motility and Polarization in Neutrophil-like HL60 Cells and Human Neutrophils

L’adaptateur 3BP2

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