BCR, NF-κB, and PI3K/AKT/mTOR deregulation in MCL. BCR engagement induces SYK phosphorylation, which in turn activates phospholipase C-γ (PLC-γ) and protein kinase C-β (PKC-β). PI3K functions as a transducer of BCR signaling and can be activated by SYK-dependent phosphorylation of CD19 and B-cell PI3K adaptor protein (BCAP). PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) on the plasma membrane to generate the second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP3). This process is reverted by PTEN. PI3K then phosphorylates PDK1 and the serine/threonine kinase AKT (Thr308) that activates mTOR (by inactivation of the inhibitor TSC1/2) and NF-κB (by activation of IKK). Only the mTOR complex 1 (mTORC1) is under AKT control and activates cap-dependent translation through S6K and 4E-BP1. mTOR complex 2 (mTORC2) can phosphorylate AKT (Ser473), increasing its kinase activity. Canonical NF-κB activation through AKT, or PKC-β involves IKK-mediated phosphorylation of the inhibitor IκBα, resulting in its proteasomal degradation and release of bound transcription factors that can then translocate to the nucleus. A20 and FAF1 inhibit NF-κB activation. The alternative pathway is activated by phosphorylation of p100 by IKKα complexes and subsequent proteasomal generation of p52. The cytokine BAFF/BLyS by binding to BAFF-R activates both canonical and noncanonical pathways. NF-κB transcription factors form heterodimers and homodimers to activate the transcription of genes involved in survival, proliferation, and apoptosis. Several steps in these signaling pathways are altered in MCL; blue symbols (Δ) indicate molecules inactivated or down-regulated; red symbols, molecules activated or overexpressed. Illustration by Paulette Dennis.