APRIL-TACI–mediated proliferation of FL cells is PI3K and mTOR dependent. (A) Karpas cells were cultured alone or with 500 nM wortmanin or 10 μM Ly294002 with or without the addition of APRIL for 48 hours, and proliferation was assessed. Data representative of 3 experiments are shown. (B) Control and Akt siRNA-transfected Karpas cells were left untreated or treated with APRIL for 48 hours, and proliferation was assessed. (C) Karpas cells were cultured alone or with APRIL or with 20 nM rapamycin or both for 48 hours, and proliferation was assessed. (D) Schematic diagram for APRIL-induced signaling through TACI in FL B cells. Malignant cells from FL express TACI, which delivers a proliferative signal upon engagement with APRIL. APRIL-TACI interactions activate the PI3K, Akt, and mTOR pathway, followed by phosphorylation of p70S6 kinase, 4E-BP1, and S6. Activation of mTOR results in up-regulation of cyclin D1 expression and Rb phosphorylation. The hypothetical TRAF proteins involved in APRIL-TACI–mediated PI3K and NF-κB activation are indicated by dashed lines.