Phosphatidylinositol 3-Kinase-Dependent Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 and NF-κB Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells

Abstract

Phosphatidylinositol 3-kinase (PI-3K) has been linked to promitogenic responses in splenic B cells following B cell Ag receptor (BCR) cross-linking; however identification of the signaling intermediates that link PI-3K activity to the cell cycle remains incomplete. We show that cyclin D2 induction is blocked by the PI-3K inhibitors wortmannin and LY294002, which coincides with impaired BCR-mediated mitogen-activated protein/extracellular signal-related kinase kinase (MEK)1/2 and p42/44ERK phosphorylation on activation residues. Cyclin D2 induction is virtually absent in B lymphocytes from mice deficient in the class IA PI-3K p85α regulatory subunit. In contrast to studies with PI-3K inhibitors, which inhibit all classes of PI-3Ks, the p85α regulatory subunit is not required for BCR-induced MEK1/2 and p42/44ERK phosphorylation, suggesting the contribution of another PI-3K family members in MEK1/2 and p42/44ERK activation. However, p85α−/− splenic B cells are defective in BCR-induced IκB kinase β and IκBα phosphorylation. We demonstrate that NF-κB signaling is required for cyclin D2 induction via the BCR in normal B cells, implicating a possible link with the defective IκB kinase β and IκBα phosphorylation in p85α−/− splenic B cells and their ability to induce cyclin D2. These results indicate that MEK1/2-p42/44ERK and NF-κB pathways link PI-3K activity to Ag receptor-mediated cyclin D2 induction in splenic B cells.