| First Author | Tran CW | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 12 | Pages | 4056-4065 |
| PubMed ID | 29109121 | Mgi Jnum | J:252647 |
| Mgi Id | MGI:6105161 | Doi | 10.4049/jimmunol.1600396 |
| Citation | Tran CW, et al. (2017) Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation. J Immunol 199(12):4056-4065 |
| abstractText | 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 Ser(476) and Ser(480) 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. |
