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1.

001-es BibID:BIBFORM054323
035-os BibID:PMID: 9533441
Első szerző:Koncz Gábor (biológus, immunológus)
Cím:FcγRIIb inhibits both B cell receptor- and CD19-induced Ca2+ mobilization in FcγR-transfected human B cells / Gábor Koncz, János Gergely, Gabriella Sármay
Dátum:1998
ISSN:0953-8178
Megjegyzések:Fc gamma RIIb (CD32) controls antibody production by down-regulating cell activation, when co-clustered with B cell antigen receptors (BOB) in vivo, via immune complexes consisting of secreted IgG and antigen, Fc gamma RIIb-BCR co-ligation in vitro was shown to inhibit the Ca2+ influx from the extracellular space, the mechanism of which is not fully understood, Human B cells express Fc gamma RIIb1 and Fc gamma RIIb2, differing only in a 19 amino acid long insert in the cytoplasmic tail of the former, To elucidate whether Fc gamma RIIb1 and Fc gamma RIIb2 isoforms show any difference in the down-regulation of B cells, we have studied the effect of co-clustering of BCR and Fc gamma RIIb1 or Fc gamma RIIb2 on the Ca2+ signaling in a Burkitt's lymphoma cell line, ST486, transfected with the two isoforms respectively, We have shown here, for the first time, that co-aggregation of BCR and Fc gamma RIIb may also inhibit Ca2+ release from the endoplasmic reticulum pool of human B cells, Both isoforms mediated this inhibition and the inhibitory effect depended on the ratio of BCR to Fc gamma RIIb cross-linking, In contrast to Fc gamma RIIb, the CD21/CD19 complex was shown to up-regulate B cell response by lowering the activation threshold, We have shown here that co-clustering of Fc gamma RIIb with CD19 inhibited the CD19-induced Ca2+ influx, Furthermore, the three party co-aggregation of Fc gamma RIIb with BCR and CD19 resulted in a decreased Ca2+ response, as compared to the BOB-plus CD19-induced one, indicating that Fc gamma RIIb may inhibit CD19-induced enhancement of B cell activation, On the basis of these data we suggest that IgG-containing and C3d-fixing immune complexes may down-regulate the B cell response by interfering with both BCR-and CD19-mediated Ca2+ mobilization.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
CD19
Fc gamma receptors
human B cells
regulation
signal transduction
Megjelenés:International Immunology. - 10 : 2 (1998), p. 141-146. -
További szerzők:Gergely János Sármay Gabriella
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2.

001-es BibID:BIBFORM054321
035-os BibID:PMID: 10382761
Első szerző:Koncz Gábor (biológus, immunológus)
Cím:Fcγ receptor-mediated inhibition of human B cell activation : the role of SHP-2 phosphatase / Gábor Koncz, Israel Pecht, János Gergely, Gabriella Sármay
Dátum:1999
ISSN:0014-2980
Megjegyzések:Co-clustering of the type II receptors binding the Fc part of IgG (Fc gamma RIIb) and B cell receptors results in the translocation of cytosolic, negative regulatory molecules to the phosphorylated immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of the FcyRIIb. SH2 domain-containing protein tyrosine phosphatases (SHP-1 and SHP-2), and the polyphosphoinositol 5'-phosphatase (SHIP) have been reported earlier to bind to murine Fc gamma RIIb P-ITIM. However, neither the functional substrates of these enzymes, nor the mechanism of the inhibition are fully resolved. We show here that the human Fc gamma RIIb binds SHP-2 when co-clustered with the B cell receptors, whereas its synthetic P-ITIM peptide bindes SHP-2 and SHIP in lysates of the Burkitt's lymphoma cell line BL41. The P-ITIM peptide binding enhances SHP-2 activity resulting in dephosphorylation and release of P-ITIM-bound SHIP and She. Moreover, P-ITIM-bound SHP-2 dephosphorylates synthetic peptides corresponding to the sites of tyrosine phosphorylation on SHIP and She, indicating that these proteins are its potential substrates. Thus SHP-2-induced dephosphorylation may modulate the intracellular localization and/or activity of SHIP and She, thereby inhibiting further activation pathways which they mediate.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
SHP-2
Fc gamma RIIb
human
B cell
Megjelenés:European Journal of Immunology. - 29 : 6 (1999), p. 1980-1989. -
További szerzők:Pecht, Israel Gergely János Sármay Gabriella
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3.

001-es BibID:BIBFORM054319
035-os BibID:PMID: 11453982
Első szerző:Koncz Gábor (biológus, immunológus)
Cím:Co-clustering of Fcγ and B cell receptors induces dephosphorylation of the Grb2-associated binder 1 docking protein / Gábor Koncz, Gábor K. Tóth, Gyöngyi Bökönyi, György Kéri, Israel Pecht, David Medgyesi, János Gergely, Gabriella Sármay
Dátum:2001
ISSN:0014-2956 1432-1033
Megjegyzések:The immunoreceptor tyrosine-based inhibitory motif (ITIM) of human type Ilb Fc gamma receptor (Fc gamma RIIb) is phosphorylated on its tyrosine upon co-clustering with the B cell receptor (BCR). The phosphorylated ITIM (p-ITIM) binds to the SH2 domains of polyphosphoinositol 5-phosphatase (SHIP) and the tyrosine phosphatase, SHP-2. We investigated the involvement of the molecular complex composed of the phosphorylated SHIP and Fc gamma RIIb in the activation of SHP-2. As a model compound, we synthesized a bisphosphopeptide, combining the sequences of p-ITIM and the N-terminal tyrosine phosphorylated motif of SHIP with a flexible spacer. This compound bound to the recombinant SH2 domains of SHP-2 with high affinity and activated the phosphatase in an in vitro assay. These data suggest that the phosphorylated Fc gamma RII-SHIP complexes formed in the intact cells may also activate SHP-2. Grb2-associated binder 1 (Gab1) is a multisite docking protein, which becomes tyrosine-phosphorylated in response to various types of signaling, including BCR. In turn it binds to the SH2 domains of SHP-2, SHIP and the p85 subunit of phosphatidyl inositol 3-kinase (PtdIns3-K) and may regulate their activity. Gab1 is a potential substrate of SHP-2, thus its binding to Fc gamma RIIb may modify the Gab1-bound signaling complex. We show here that Gab1 is part of the multiprotein complex assembled by Fc gamma RIIb upon its co-clustering with BCR. Gab1 may recruit SH2 domain-containing molecules to the phosphorylated Fc gamma RIIb. SHP-2, activated upon the binding to Fc gamma RIIb-SHIP complex, partially dephosphorylates Gab1, resulting in the release of PtdIns3-K and ultimately in the inhibition of downstream activation pathways in BCR/Fc gamma RIIb co-aggregated cells.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
B-lymphocytes
Fc gamma receptors IIb
signal transduction
Megjelenés:European Journal of Biochemistry. - 268 : 14 (2001), p. 3898-3906. -
További szerzők:Tóth Gábor K. Bökönyi Gyöngyi Kéri György Pecht, Israel Medgyesi Dávid Gergely János Sármay Gabriella
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4.

001-es BibID:BIBFORM054309
035-os BibID:PMID: 11897497
Első szerző:Kövesdi Dorottya
Cím:Developmental differences in B cell receptor-induced signal transduction / Dorottya Kövesdi, Gábor Koncz, Roland Iványi-Nagy, Yael Caspi, Masamichi Ishiai, Tomohiro Kurosaki, János Gergely, Joseph Haimovich, Gabriella Sármay
Dátum:2002
ISSN:0898-6568
Megjegyzések:We have compared early signaling events at various stages of B cell differentiation using established mouse cell lines. Clustering of pre-B cell antigen receptor (BCR) or BCR induced the tyrosine phosphorylation of various proteins in all cells, although the phosphorylation pattern differed. In spite of the pre-BCR-induced tyrosine phosphorylation, we could not detect an intracellular Ca(2+) signal in pre-B cells. However. coclustering of the pre-BCR with CD19 did induce Ca(2+) mobilization. In contrast to the immature and mature B cells, where the B cell linker protein (BLNK) went through inducible tyrosine phosphorylation upon BCR clustering, we observed a constitutive tyrosine phosphorylation of BLNK in pre-B cell lines. Both BLNK and phospholipase C (PLC)gamma were raft associated in unstimulated pre-B cells, and this could not be enhanced by pre-BCR engagement, suggesting a ligand-independent PLC-gamma-mediated signaling. Further results indicate that the cell lines representing the immature stage are more sensitive to BCR-, CD19- and type II receptors binding the Fe part of IgG (FcgammaRIIb)mediated signals than mature B cells.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
B cell
development
receptors
signaling
tyrosine phosphorylation
Megjelenés:Cellular Signalling. - 14 : 6 (2002), p. 563-572. -
További szerzők:Koncz Gábor (1970-) (biológus, immunológus) Iványi-Nagy Roland Caspi, Yael Ishiai, Masamichi Kurosaki, Tomohiro Gergely János Haimovich, Joseph Sármay Gabriella
Pályázati támogatás:Bolyai János Kutatási Ösztöndíj
Egyéb
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5.

001-es BibID:BIBFORM054320
Első szerző:Kurucz István
Cím:Bacterially expressed human FcγRIIb is soluble and functionally active after in vitro refolding / István Kurucz, Ágnes Hilbert, Attila Kapus, Dávid Medgyesi, Gábor Koncz, Gabriella Sármay, Anna Erdei, János Gergely
Dátum:2000
ISSN:0165-2478
Megjegyzések:A recombinant soluble form of the human Fc gamma receptor was produced by engineering a cDNA construct containing the extracellular part of the mature protein. After expression in bacteria as inclusion body, the polypeptide was highly purified and was refolded in vitro with a method that was developed for the renaturation of immunoglobulin fragments. With this method oxidation of the disulfide bridges within the domains of the protein is done in the presence of an artificial 'chaperone' which protects the polypeptide molecules from unwanted protein-protein interactions thereby inhibiting the incorrect oxidation of the SH-groups, and misfolding of the protein. The refolded recombinant soluble Fc gamma RIIb showed several characteristics of the native receptor: (i) it was recognized by a series of monoclonal antibodies specific for, and in most cases produced against the native cell-surface receptor; (ii) it is bound to its ligand (the Fc-region of different immunoglobulins) under very diverse conditions; and (iii) it is competed strongly and specifically with the native cell surface receptor for both ligand and antibody binding in experiments with distinct read-outs; (iv) monoclonal antibodies produced against the recombinant protein specifically recognized Fc gamma RIIb on different cells. From these data it was concluded that the recombinant soluble Fc-receptor was in a native, functionally active form, and its function was not affected by the lack of glycosylation. (C) 2000 Elsevier Science B.V. All rights reserved.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
soluble Fc gamma receptors
bacterial expression
refolding
Megjelenés:Immunology Letters. - 75 : 1 (2000), p. 33-40. -
További szerzők:Hilbert Ágnes Kapus Attila Medgyesi Dávid Koncz Gábor (1970-) (biológus, immunológus) Sármay Gabriella Erdei Anna Gergely János
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6.

001-es BibID:BIBFORM054306
Első szerző:Medgyesi Dávid
Cím:Functional mapping of the FcγRII binding site on human IgG1 by synthetic peptides / Dávid Medgyesi, Katalin Uray, Krisztina Sallai, Ferenc Hudecz, Gábor Koncz, Jakub Abramson, Israel Pecht, Gabriella Sármay, János Gergely
Dátum:2004
ISSN:0014-2980
Megjegyzések:Receptors specific for the Fc part of IgG (FcgammaR) are expressed by several cell types and play diverse roles in immune responses. Impaired function of the activating and inhibitory FcgammaR may result in autoimmunity. Thus, the modulation of IgG-FcgammaR interaction can be a target for the development of treatments for some autoimmune and inflammatory diseases. This study addresses the localization and functional characterization of linear sequences in human IgG1 which bind to FcgammaRII. Peptides with overlapping sequences derived from the CH2 domain of human IgG1 between P(234) and S(298) were synthesized and used in binding and functional experiments. Binding of the peptides to FcgammaR was assayed in vitro and ex vivo, and peptides found to interact were functionally tested. The shortest effective peptide was T(216)-p(271) which bound to soluble recombinant Fc-gammaRIIb with K(d)=6x10(6) M(-1). The biotinylated peptides R(255)-p(271) and T(256)-p(271) complexed by avidin exhibited functional activity; they induced FcgammaRIIb-mediated inhibition of the BCR-triggered Ca(2+) response of human Burkitt lymphoma cells, and inflammatory cytokine production (TNF-alpha and IL-6) by the human monocyte cell line MonoMac. In conclusion, our results suggest that the selected peptides functionally represent the Fc-gammaRII-binding part of IgG1.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
IgG
Fc gamma Re
fc peptide
binding site
Megjelenés:European Journal of Immunology. - 34 : 4 (2004), p. 1127-1135. -
További szerzők:Uray Katalin Sallai Krisztina Hudecz Ferenc Koncz Gábor (1970-) (biológus, immunológus) Abramson, Jakub Pecht, Israel Sármay Gabriella Gergely János
Pályázati támogatás:AKP 2000-40 3,3
MTA
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7.

001-es BibID:BIBFORM054348
035-os BibID:PMID: 7843241
Első szerző:Sármay Gabriella
Cím:The alternative splicing of human FcγRII mRNA is regulated by activation of B cells with mIgM cross-linking, interleukin-4, or phorbolester / Gabriella Sármay, Zoltán Rozsnyay, Gábor Koncz, Alla Danilkovich, János Gergely
Dátum:1995
ISSN:0014-2980
Megjegyzések:The human type two IgG binding receptors (Fc gamma RII) are encoded by three genes (Fc gamma RIIA, -B and C) resulting in at least six protein isoforms generated by alternative mRNA splicing. Surface expression of Fc gamma RTT has been shown to be modulated during B cell activation, although data characterizing the isoform(s) expressed are not available. The extracellular as well as the transmembrane domains of various Fc gamma RII are highly homologous. Only the intracellular domains vary between the different Fc gamma RII isoforms, suggesting differences in signal transduction. Using reverse transcriptase and polymerase chain reaction of mRNA obtained from resting tonsil B cells,we show that the majority of Fc gamma RII mRNA species to be of b2 type, although b1 type and a low level of Fc gamma RIIa type are also present. Culturing the cells for 18 h in the presence of 2.5 U/ml interleukin-4 or 10 mu g/ml affinity-purified anti-IgM F(ab')(2) fragments induced a switch in alternative splicing, resulting in a significant increase of Fc gamma RIIb1 mRNA expression, while the synthesis of Fc gamma RIIb2 mRNA was down-regulated. Stimulation of B cells with 100 ng/ml phorbol 12-myristate 13-acetate induced similar alteration, although only after 48-h treatment. The accumulation of Fc gamma RIIb1 and the reduction of both Fc gamma IIb2 and Fc gamma IIa mRNA in activated cells is accompanied by the enhanced expession of Fc gamma RII on the cell surface, representing most probably the Fc gamma RIIb1 isoform. Heat-aggregated IgG inhibited the anti-IgM-induced proliferation of resting but not that of activated B cells, suggesting that aggregation of Fc gamma RIIb2 constitutively expressed on resting B cells might be responsible for the prevention of inadequate activation of resting B cells.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
FC-GAMMA-RIIB
B CELLS
REGULATION
Megjelenés:European Journal of Immunology. - 25 : 1 (1995), p. 262-268. -
További szerzők:Rozsnyay Zoltán Koncz Gábor (1970-) (biológus, immunológus) Danilkovich, Alla Gergely János
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8.

001-es BibID:BIBFORM054331
035-os BibID:PMID: 7797241
Első szerző:Sármay Gabriella
Cím:Interaction of signaling molecules with human FcγRIIb1 and the role of various FcγRIIb isoforms in B-cell regulation / Gabriella Sarmay, Zoltan Rozsnyay, Gabor Koncz, Janos Gergely
Dátum:1995
ISSN:0165-2478
Megjegyzések:The low-affinity type-IIb IgG Fc-binding receptors (Fc gamma RIIb) are expressed on B cells. When cross-linked with mIgM Fc gamma RIIb are known to down-regulate B-cell activation by interrupting signal transduction upstream from G-protein-activated events. We have studied Fc gamma RII isoforms expressed on resting and activated B cells and the interaction of Fc gamma RIIb1 with molecules transducing the antigen receptor-mediated signals. Expression of Fc gamma RII isoforms was studied by reverse transcription and polymerase chain reaction. Resting B cells express both Fc gamma RIIb2 and Fc gamma RIIb1 isoforms. Activation with anti-IgM or IL-4 induces the splicing of Fc gamma RIIb1 mRNA, while the alternative splicing of Fc gamma RIIb2 mRNA is down-regulated, resulting in the surface expression of Fc gamma RIIb1. Functional differences were found between the two isoforms in-inhibiting B-cell activation, suggesting that Fc gamma RIIb2 might influence the threshold of signals necessary for activation of resting B cells, while Fc gamma RIIb1 may regulate in later phases of antibody response.To explore the mechanism by which Fc gamma RII may uncouple antigen receptor-mediated signal transduction, we have investigated the association of signaling molecules with Fc gamma RII. Beside the protein tyrosine kinase (PTK) fyn, protein kinase C (PKC) was found to be co-isolated with Fc gamma RIIb1, suggesting a tight connection between these kinases and Fc gamma RII. We suggest that PKC might be responsible for the activation-induced phosphorylation of Fc gamma RII on serine residues. Signaling molecules responsible for the activation and localization of further elements of the activation pathway were also found to associate with Fc gamma RII. Among these RasGAP and Shc, the adapter molecule connecting PTK-triggered events to the Ras activation-dependent pathway were characterized. We suggest that Fc gamma RII may compete with the B-cell antigen receptor for key molecules regulating Ras activity, inhibiting thereby Ras activation.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
HUMAN LYMPHOCYTES-B
RECEPTOR
PROTEIN
PHOSPHORYLATION
EXPRESSION
ACTIVATION
Megjelenés:Immunology Letters. - 44 : 2-3 (1995), p. 125-131. -
További szerzők:Rozsnyay Zoltán Koncz Gábor (1970-) (biológus, immunológus) Gergely János
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9.

001-es BibID:BIBFORM054328
Első szerző:Sármay Gabriella
Cím:Human Type II Fcγ Receptors Inhibit B Cell Activation by Interacting with the p21ras-dependent Pathway / Gabriella Sármay, Gábor Koncz, János Gergely
Dátum:1996
ISSN:0021-9258 1083-351X
Megjegyzések:Co-ligation of antigen receptors and type II Fc gamma receptors (Fc gamma RIIb) on B cells interrupts signal transduction and ultimately inhibits antibody production. We have identified p52 She in the Fc gamma RIIb1-specific immunoprecipitates isolated from the membrane fraction of BL41 Burkitt lymphoma cells following B cell receptor-Fc gamma RIIb1 co-ligation. The insolubilized synthetic peptide representing the phosphorylated form of the tyrosine-based inhibitory moth of Fc gamma RIIb also binds She from the lysates of activated but not from resting BL41 cells. This suggests that the binding does not depend on the interaction of Fc gamma RIIb1-phosphotyrosine with the SH2 domain of She. Tyr phosphorylation of Fc gamma RIIb1-associated She is low, indicating an impaired function. She is implicated in regulating p21(ras) activation; thus, we have compared p21(ras) activities in BL41 cells treated in different ways. p21(ras) activity is reduced when B cell receptor and Fc gamma RIIb1 are co-ligated. p21(ras) couples protein-tyrosine kinase-dependent events to the Ser/Thr kinase-mediated signaling pathway leading to the activation of mitogen-activated protein kinases (MAPK). Our results show that B cell receptor-Fc gamma RIIb1 co-crosslinking partially inhibits mitogen-activated protein kinase activity. We conclude that Fc gamma RIIb1-dependent inhibition of human B cell activation may be based on interrupting signal transduction between protein-tyrosine kinases and the p21(ras)/mitogen-activated protein kinase-dependent activation pathway.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
PROTEIN-KINASE-C
CROSS-LINKING
TYROSINE PHOSPHORYLATION
LYMPHOCYTES
SHC
IMMUNOGLOBULIN
P21(RAS)
COMPLEX
FC-GAMMA-RIIB1
STIMULATION
Megjelenés:The Journal of Biological Chemistry. - 271 : 48 (1996), p. 30499-30504. -
További szerzők:Koncz Gábor (1970-) (biológus, immunológus) Gergely János
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10.

001-es BibID:BIBFORM054325
035-os BibID:PMID: 9052860
Első szerző:Sármay Gabriella
Cím:Integration of activatory and inhibitory signals in human B-cells / Gabriella Sármay, Gábor Koncz, János Gergely
Dátum:1996
ISSN:0165-2478
Megjegyzések:Fc gamma receptors type IIb1 (Fc gamma RIIb1) inhibit B-cell activation when co-ligated with B-cell antigen receptors (BCR) by immune complexes. In murine B-cells the inhibition is mediated by the interaction of the phosphorylated immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of Fc gamma RIIb1 with the SH2 domain containing protein tyrosine phosphatase, SHP1. To clarify the mechanism of Fc gamma RIIb mediated inhibition of human B-cells we have studied the association of signaling molecules with human Fc gamma RIIb1 after co-ligating with BCR. Fc gamma RIIb1 were affinity purified from the Burkitt lymphoma cell line, BL41. Several tyrosine phosphorylated proteins were co-isolated with Fc gamma RIIb1 at 145, 110, and 50-60 kDa, which were not present in Fc gamma RIIb1 free immune complexes. Among these molecules we have identified the p52 She adaptor protein. Furthermore, we have shown that the insolubilised synthetic peptide corresponding P-ITIM bound She, Lyn and the p75 and p110 unidentified tyrosine phosphorylated proteins. Here we describe that the cell membrane associated She is partially dephosphorylated in BCR-Fc gamma RIIb1 co-ligated samples, suggesting that its function in regulating p21ras monomeric G protein is impaired. Indeed, we have detected a lower p21ras activity in BCR-Fc gamma RIIb1 co-crosslinked samples. These data indicate that co-ligation of BCR and Fc gamma RIIb1 interrupts signal transduction between protein tyrosine kinase activation and p21ras mediated activation pathway. Since in contrast to the mouse B-cells both Fc gamma RIIb1 and Fc gamma RIIb2 are expressed in human B-cells, we have investigated the inhibitory function of the two receptors in Fc gamma RIIb negative Burkitt lymphoma cell line ST486 transfected with Fc gamma RIIb1 and Fc gamma RIIb2, respectively. Both Fc gamma RIIb1 and Fc gamma RIIb2 inhibited the rise of intracellular Ca2+ induced by the crosslinking of BCR. The rate of the inhibition depended on the ratio of the co-crosslinked receptors (BCR-Fc gamma RIIb1) to the crosslinked BCR (BCR-BCR). Co-crosslinking of the two receptors inhibited not only the capacitive Ca2+ entry but rather the total Ca2+ response in both Fc gamma RIIb1 and Fc gamma RIIb2 transfected human B-cells. CD19 represents the signal transduction unit of complement receptor, CR2 (CD21), and is responsible for the complement activating IgM-immune complex induced enhancement of B-cell activation. Co-crosslinking of CD19 and BCR was shown to enhance B-cell activation due to the recruitment of further signaling molecules to the activator complex by the phosphorylated tyrosine residues of CD19. Here we show a novel finding that co-ligation of CD19 with Fc gamma RIIb1 inhibits the CD19-induced upregulation of Ca2+ response. The results indicate that IgG plus complement containing immune complexes may inhibit B-cell activation in vivo, due to the Fc gamma RIIb1-mediated interruption of signal transduction via both BCR and CD19.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Fc gamma RIIb
human B-cells
regulation
signal transduction
Megjelenés:Immunology Letters. - 54 : 2-3 (1996), p. 93-100. -
További szerzők:Koncz Gábor (1970-) (biológus, immunológus) Gergely János
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11.

001-es BibID:BIBFORM054324
035-os BibID:PMID: 9232445
Első szerző:Sármay Gabriella
Cím:Fcγ receptor type IIb induced recruitment of inositol and protein phosphatases to the signal transductory complex of human B-cell / Gabriella Sarmay, Gábor Koncz, Israel Pecht, János Gergely
Dátum:1997
ISSN:0165-2478
Megjegyzések:Co-clustering of Fc gamma RIIb and B-cell receptor (BCR) inhibits cell activation by interrupting BCR stimulated signal transduction. The immunoreceptor tyrosine-based inhibitory motif (ITIM) of Fc gamma RIIb becomes tyrosyl phosphorylated (P-ITIM) upon co-clustering with BCR then P-ITIM interacts with several signalling molecules, some of which negatively regulate the cell activation process. The molecules recruited by the P-ITIM of human Fc gamma RIIb have not been characterised yet. In order to affinity isolate the potential functional partner molecules of human Fc gamma RIIb, synthetic peptides were designed to cover almost the entire intracellular Fc gamma RIIb domain, including Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences and stretches containing the phosphorylated and non-phosphorylated ITIM. We report here that several tyrosyl phosphorylated proteins bind to the P-ITIM peptide from both resting and activated B-cell lysates, the 53-56 kDa being the most prominent one. A fraction of the 53-56 kDa bands were identified as the protein tyrosine kinase (PTK), Lyn which also bound to ITIM peptide, pointing to its role in initiating Fc gamma RIIb-mediated negative regulation. Among the P-ITIM associated tyr phosphorylated components, the 145 kDa one was identified as the inositol polyphosphate 5-phosphatase, SHIP and the 72 kDa protein as the protein tyrosine phosphatase (PTP) SHP2; whereas SHP1 was not detected. Phosphatase activity assays showed that P-ITIM bound about five times higher SHIP and four times higher PTP activity than the ITIM containing peptide. Furthermore, we detected PKC and MAPK in both ITIM and P-ITIM peptides precipitated samples. Since human B-cells express both Fc gamma RIIb1 and Fc gamma RIIb2, differing in a 19 amino acid insert in the cytoplasmic tail of the former, we investigated the components binding to Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences. Synthetic peptide representing Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences weakly bound unidentified tyr phosphorylated proteins at 50-56 kDa, while the insert itself did not bind a detectable amount of protein. Neither of the ITIM or P-ITIM bound molecules were observed in samples precipitated with peptides corresponding to Fc gamma RIIb1 or Fc gamma RIIb2 specific sequences. These observations suggest that protein kinases associate with both ITIM and P-ITIM of human Fc gamma RIIb, Lyn being responsible for the tyrosyl phosphorylation of ITIM. SHIP and SHP2 phosphatases selectively bind to the phosphorylated ITIM. Based on these data we assume that SHIP and SHP2 recruited in vivo to the Fc gamma RIIb co-clustered BCR are responsible for the Fc gamma RIIb mediated negative regulation of human B-cell activation.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
human B-lymphocytes
Fc gamma RIIb
phosphatases
signal transduction
regulation
Megjelenés:Immunology Letters. - 57 : 1-3 (1997), p. 159-164. -
További szerzők:Koncz Gábor (1970-) (biológus, immunológus) Pecht, Israel Gergely János
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:

12.

001-es BibID:BIBFORM054322
Első szerző:Sármay Gabriella
Cím:Cooperation between SHP-2, phosphatidyl inositol 3-kinase and phosphoinositol 5-phosphatase in the FcγRIIb mediated B cell regulation / Gabriella Sármay, Gábor Koncz, Israel Pecht, János Gergely
Dátum:1999
ISSN:0165-2478
Megjegyzések:Go-clustering B cell receptors (BCR) and type II receptors binding the Fc part of IgG (Fc gamma RIIb) inhibits B cell activation and antibody production. Tyrosine phosphorylation of an intracellular motif of Fc gamma RIIb has been shown to be a prerequisite of the inhibition. After being phosphorylated by BCR-activated tyrosine kinases, the immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of Fc gamma RIIb recruits SH2 domain containing protein tyrosine phosphatase(s) (PTPs) and polyphosphoinositol 5-phosphatase (SHIP) to the vicinity of BCR, which in turn dephosphorylate their specific substrates. This leads to the interruption of signal transduction, consequently to the anergy and/or apoptosis of the cell. The downstream signaling pathways affected by Fc gamma RIIb-BCR co-clustering are not clarified yet, neither the substrates of PTPs are known. We have studied the Fc gamma RIIb mediated B cell inhibition on human Burkitt lymphoma cell line (BL41). From the lysates of BL41 cells SHP-2 and phosphatidylinositol 3-kinase (PI3-K), as well as the protein tyrosine kinase (PTK) Lyn bind both to the BCR-co-clustered Fc gamma RIIb and to its P-ITIM peptide. Lyn hyperphosphorylates the P-ITIM associated molecules, including SHIP in the in vitro protein tyrosine kinase activity assay. The P-ITIM-compelled multi-phosphoprotein complex binds to and activates SHP-2, which in turn dephosphorylates SHIP and Shc and probably other substrates. Subcellular localisation of these signaling molecules is regulated by the phosphotyrosin-SH2 domain interactions, thus dephosphorylation may result in the re-direction of Shc and SHIP within the cell, consequently, in the modulation of their activity. Finally, co-clustering Fc gamma RIIb and BCR or Fc gamma RIIb and CD19 on the intact cells inhibited PI3-K activity as detected in the anti-phosphotyrosine (anti-PY) precipitates. The results indicate that SHP-2 bound to and activated by the BCR co-clustered Fc gamma RIIb, may down-regulate PI3-K activity by dephosphorylating a yet unidentified regulatory molecule, which recruits PI3-K to the cell membrane.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
human Fc gamma RIIb
B cell regulation
SHP-2
PI3-K
Megjelenés:Immunology Letters. - 68 : 1 (1999), p. 25-34. -
További szerzők:Koncz Gábor (1970-) (biológus, immunológus) Pecht, Israel Gergely János
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
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