T lymphocytes use several specialized mechanisms to induce apoptotic cell death. The tumor necrosis factor (TNFbrelated family of membrane-anchored and secreted ligands represent a major mechanism regulating cell death and cell survival. These ligands also coordinate differentiation of tissue to defend against intracellular pathogens and regulate development of lymphoid tissue. Cellular responses are initiated by a corresponding family of specific receptors that includes two distinct TNFR (TNFR60 and TNFRSO), Fas (CD95), CD40, p75NTF, and the recently identified lymphotoxin p-receptor (LTPR), among others. The MHC-encoded cytokines, TNF and LTa, form homomeric trimers, whereas LTP assembles into heterotrimers with LTa, creating multimeric ligands with distinct receptor specificities. The signal transduction cascade is initiated by transmembrane aggregation (clustering) of receptor cytoplasmic domains induced by binding to their multivalent ligands. The TRAF family of Zn RING/finger proteins bind to TNFRSO; CD40 and LTPR are involved in induction NFKB and cell survival. TNFR6O and Fas interact with several distinct cytosolic proteins sharing the "death domain" homology region. TNF binding to TNFR60 activates a serine protein kinase activity and phosphoproteins are recruited to the receptor forming a multicomponent signaling complex. Thus, TNFRs use diverse sets of signaling molecules to initiate and regulate cell death and survival pathways. a 1996 WiIey-Liss, ~n c .
Key words: Death domain, ring