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- W4313359551 startingPage "48.4" @default.
- W4313359551 abstract "Abstract We have recently shown (Luo et al., Immunity, in press) that, compared to naïve B cells (NBC), both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBC). BCR signaling in GCBC induces only transient activation of Syk, leading to partial activation of the PI3K-AKT pathway, generating p-Foxo1 but not p-S6. There is minimal BCR-directed activation of other downstream pathways such as NF-κB. Conversely for CD40 ligation, only NF-κB but not PI3K is activated in GCBC. Initially we found that Lyn, the most upstream kinase in the BCR cascade, has more inhibitory vs activating phosphorylation in GCBC. To understand how this occurs, and why AKT targets only selected substrates in GCBC, we used an AKT-substrate-specific mAb to immunoprecipitate AKT targets in GCBC. We analyzed these by mass spectrometry to identify potential GCBC-specific AKT targets. This analysis revealed that AKT itself was retargeted in GCBC compared to NBC. In GCBC, AKT appeared to preferentially target negative regulators, including CSK, a kinase of the inhibitory Tyr of Lyn. In vitro kinase and functional studies confirmed that AKT could phosphorylate CSK. We then demonstrated that this phosphorylation results in markedly increased CSK enzymatic activity to phosphorylate Lyn. Consistent with this, we found Lyn activity in GC B cells is inhibited by CSK catalyzed phosphorylation. Critically, inhibiting AKT substantially enhanced activation vs inhibitory Tyr phosphorylation of Lyn, and enhanced Syk phosphorylation and downstream signals upon BCR stimulation in GCBC. Taken together, our findings identify and document a unique AKT negative feedback loop that dampens proximal BCR signaling in GC B cells." @default.
- W4313359551 created "2023-01-06" @default.
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- W4313359551 date "2018-05-01" @default.
- W4313359551 modified "2023-09-25" @default.
- W4313359551 title "AKT targets CSK to regulate proximal BCR signaling in germinal center B cells" @default.
- W4313359551 doi "https://doi.org/10.4049/jimmunol.200.supp.48.4" @default.
- W4313359551 hasPublicationYear "2018" @default.
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