Signaling in Human B-Lymphoma Rafts

Abstract

In normal and tumoral B-lymphocytes, proximal signaling requires assemblies of proteins to generate pro- survival and anti-apoptotic information. B-cell receptor (BCR) engagement by antigen results in the formation of raft- based microclusters that incorporate the Lyn kinase. Further involvement of the Syk kinase and the B-cell linker (BLNK) adaptor depend on the kinase activity of Lyn to phosphorylate specific motifs in the cytoplasmic portion of the BCR complex, and to maintain this complex in its open conformation. Signaling proceeds by way of phospholipase-C acti- vation, protein kinase C activation and phosphorylation of the caspase-recruitement domain (CARD)-membrane- associated guanylate kinase (MAGUK) protein-1 (CARMA1) protein. Oligomerization of phosphorylated CARMA1 proteins generates a CARMA1 signalosome, which is anchored in rafts and permits phosphorylation of the inhibitor of nuclear factor kappa-B (NF- B), its degradation in the proteasome and activation of NF- B. Constitutively active signalo- somes have been identified in B-lymphoma cell membranes that either lock the Lyn kinase in a permanently active confi- guration by association with the Csk-binding protein (Cbp) Cbp/phosphoprotein associated with glycosphingolipid-rich domains (PAG) adaptor, or maintain the CD40 receptor permanently active by engagement with its ligand CD154. The constitutively active Lyn is directly connected with pro-survival and anti-apoptotic pathways, as Lyn inhibition results in lymphoma cell death and the CD40-CD40 ligand signalosome sends co-stimulatory signals via the NF- B pathway. The constitutively active signalosomes exploit raft microdomains to assemble signaling proteins that generate inappropriately durable signals. Such signalosomes reflect the dependence of lymphoma cells on a narrow spectrum of signaling proteins for the generation of survival signals, and could be exploited therapeutically.