Assembly of post-receptor signaling complexes for the tumor necrosis factor receptor superfamily

The tumor necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins that are structurally related in their extracellular domains and specifically activated by the corresponding superfamily of TNF-like ligands. Members of this receptor superfamily are widely distributed and play important roles in many crucial biological processes such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis. A remarkable dichotomy of the TNFR superfamily is the ability of these receptors to induce the opposing effects of gene transcription for cell survival, proliferation, and differentiation and of apoptotic cell death. The intracellular signaling proteins known as TNF receptor associated factors (TRAFs) are the major signal transducers for the cell survival effects, while the death-domain-containing proteins mediate cell death induction. This review summarizes recent structural, biochemical, and functional studies of these signal transducers and proposes the molecular mechanisms of the intracellular signal transduction.