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1.

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
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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2.

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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DOI
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3.

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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4.

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
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5.

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
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