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Article: Glycogen synthase kinase-3 modulates Cbl-b and constrains T cell activation

TitleGlycogen synthase kinase-3 modulates Cbl-b and constrains T cell activation
Authors
Issue Date2017
Citation
Journal of Immunology, 2017, v. 199, n. 12, p. 4056-4065 How to Cite?
AbstractCopyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K-protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K-PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity. In this study, we further examined the molecular pathway linking PKB and Cbl-b in murine models. Our data show that the protein kinase GSK-3, one of the first targets identified for PKB, catalyzes two previously unreported phosphorylation events at Ser476 and Ser480 of Cbl-b. GSK-3 inactivation by PKB abrogates phosphorylation of Cbl-b at these two sites and results in reduced Cbl-b protein levels. We further show that constitutive activation of PKB in vivo results in a loss of tolerance that is mediated through the downregulation of Cbl-b. Altogether, these data indicate that the PI3K-PKB-GSK-3 pathway is a novel regulatory axis that is important for controlling the decision between T cell activation and tolerance via Cbl-b.
Persistent Identifierhttp://hdl.handle.net/10722/293055
ISSN
2023 Impact Factor: 3.6
2023 SCImago Journal Rankings: 1.558
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTran, Charles W.-
dc.contributor.authorSaibil, Samuel D.-
dc.contributor.authorBihan, Thierry Le-
dc.contributor.authorHamilton, Sara R.-
dc.contributor.authorLang, Karl S.-
dc.contributor.authorYou, Han-
dc.contributor.authorLin, Amy E.-
dc.contributor.authorGarza, Kristine M.-
dc.contributor.authorElford, Alisha R.-
dc.contributor.authorTai, Kelly-
dc.contributor.authorParsons, Michael E.-
dc.contributor.authorWigmore, Kip-
dc.contributor.authorVainberg, Mitchell G.-
dc.contributor.authorPenninger, Josef M.-
dc.contributor.authorWoodgett, James R.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorOhashi, Pamela S.-
dc.date.accessioned2020-11-17T14:57:46Z-
dc.date.available2020-11-17T14:57:46Z-
dc.date.issued2017-
dc.identifier.citationJournal of Immunology, 2017, v. 199, n. 12, p. 4056-4065-
dc.identifier.issn0022-1767-
dc.identifier.urihttp://hdl.handle.net/10722/293055-
dc.description.abstractCopyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K-protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K-PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity. In this study, we further examined the molecular pathway linking PKB and Cbl-b in murine models. Our data show that the protein kinase GSK-3, one of the first targets identified for PKB, catalyzes two previously unreported phosphorylation events at Ser476 and Ser480 of Cbl-b. GSK-3 inactivation by PKB abrogates phosphorylation of Cbl-b at these two sites and results in reduced Cbl-b protein levels. We further show that constitutive activation of PKB in vivo results in a loss of tolerance that is mediated through the downregulation of Cbl-b. Altogether, these data indicate that the PI3K-PKB-GSK-3 pathway is a novel regulatory axis that is important for controlling the decision between T cell activation and tolerance via Cbl-b.-
dc.languageeng-
dc.relation.ispartofJournal of Immunology-
dc.titleGlycogen synthase kinase-3 modulates Cbl-b and constrains T cell activation-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.4049/jimmunol.1600396-
dc.identifier.pmid29109121-
dc.identifier.scopuseid_2-s2.0-85038584204-
dc.identifier.volume199-
dc.identifier.issue12-
dc.identifier.spage4056-
dc.identifier.epage4065-
dc.identifier.eissn1550-6606-
dc.identifier.isiWOS:000417018100014-
dc.identifier.issnl0022-1767-

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