The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells

Compared to naïve B cells (NBCs), both B cell antigen receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to optimize selection for high-affinity B cells. The mechanism for BCR reprogramming in GCBCs remains unknown. We describe a GC-specific, AKT kinase-driven negative feedback loop that attenuates BCR signaling. A mass spectrometry proteomic approach revealed that AKT activity was retargeted in GCBCs compared to NBCs. Retargeting was linked to differential AKT T308 and S473 phosphorylation, in turn due to GC-specific upregulation of phosphoinositide-dependent protein kinase PDK1 and the phosphatase PTEN, which retuned phosphatidylinositol-3-OH kinase (PI3K) signals. In GCBCs, AKT preferentially targeted CSK, SHP-1 and HPK1, which are negative regulators of BCR signaling. Phosphorylation results in markedly increased enzymatic activity of these proteins, creating a negative-feedback loop that dampens upstream BCR signaling. Inhibiting AKT substantially enhanced activation of BCR proximal kinase LYN as well as downstream BCR signaling molecules in GCBCs, establishing the relevance of this pathway.