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Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy

B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (...

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Autores principales: Franks, S. Elizabeth, Cambier, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897502/
https://www.ncbi.nlm.nih.gov/pubmed/29681901
http://dx.doi.org/10.3389/fimmu.2018.00665
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author Franks, S. Elizabeth
Cambier, John C.
author_facet Franks, S. Elizabeth
Cambier, John C.
author_sort Franks, S. Elizabeth
collection PubMed
description B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors. Conversely, in anergic B cells, chronic antigen stimulation drives biased monophosphorylation of CD79 ITAMs leading to recruitment of Lyn, but not Syk, which docks only to bi-phosphorylated ITAMS. In this context, Lyn appears to function primarily as a driver of inhibitory signaling pathways promoting the inhibition of the PI3K pathway by inositol phosphatases, SHIP-1 and PTEN, which hydrolyze PIP3 to PIP2. Lyn may also exert negative regulation of signaling through recruitment of SHP-1, a tyrosine phosphatase that dephosphorylates activating signaling molecules. Alleles of genes that encode or regulate expression of components of this axis, including SHIP-1, SHP-1, Csk/PTPn22, and Lyn, have been shown to confer risk of autoimmunity. This review will discuss functional interplay of components of this pathway and the impact of risk alleles on its function.
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spelling pubmed-58975022018-04-20 Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy Franks, S. Elizabeth Cambier, John C. Front Immunol Immunology B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors. Conversely, in anergic B cells, chronic antigen stimulation drives biased monophosphorylation of CD79 ITAMs leading to recruitment of Lyn, but not Syk, which docks only to bi-phosphorylated ITAMS. In this context, Lyn appears to function primarily as a driver of inhibitory signaling pathways promoting the inhibition of the PI3K pathway by inositol phosphatases, SHIP-1 and PTEN, which hydrolyze PIP3 to PIP2. Lyn may also exert negative regulation of signaling through recruitment of SHP-1, a tyrosine phosphatase that dephosphorylates activating signaling molecules. Alleles of genes that encode or regulate expression of components of this axis, including SHIP-1, SHP-1, Csk/PTPn22, and Lyn, have been shown to confer risk of autoimmunity. This review will discuss functional interplay of components of this pathway and the impact of risk alleles on its function. Frontiers Media S.A. 2018-04-06 /pmc/articles/PMC5897502/ /pubmed/29681901 http://dx.doi.org/10.3389/fimmu.2018.00665 Text en Copyright © 2018 Franks and Cambier. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Franks, S. Elizabeth
Cambier, John C.
Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
title Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
title_full Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
title_fullStr Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
title_full_unstemmed Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
title_short Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
title_sort putting on the brakes: regulatory kinases and phosphatases maintaining b cell anergy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897502/
https://www.ncbi.nlm.nih.gov/pubmed/29681901
http://dx.doi.org/10.3389/fimmu.2018.00665
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