T Cell Receptor-induced NF-KB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b via Akt- and PKC-theta-dependent Pathways (87.10)

Abstract

Abstract Previously, we demonstrated that Cbl-b tunes the threshold for T cell activation mediated by CD28 and CTLA-4. Cbl-b negatively regulates Vav-1 via a PI3-K-dependent mechanism. However, it is unknown whether Cbl-b also targets other signaling pathway(s). In this study, we found that loss of Cbl-b selectively results in aberrant activation of TCR-induced NF-κB which is mediated by PI3-K/Akt and PKC-𝛉. The absence of Cbl-b also results in enhanced TCR-induced activation of PLC-γ1 which may selectively induce activation of PKCs including PKC-𝛉 but not Ca2+ signaling pathway. Cbl-b associates with PKC-𝛉 upon TCR stimulation and regulates TCR-induced PKC-𝛉 activation through Vav-1 which couples PKC-𝛉 to PI3-K and allows it to be phosphorylated possibly by PDK-1. PKC-𝛉 then couples IKKs to CBM complex, resulting in activation of IKK complex. Therefore, our data first demonstrate that down-regulation of TCR-induced NF-κB activation by Cbl-b is coordinately mediated by both Akt- and PKC-𝛉dependent signaling pathways in primary T cells.