Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death

Abstract

The signaling pathways that regulate cell survival are beginning to be defined. Receptors such as Fas and tumor necrosis factor receptor type I (TNFRI) have been shown to be capable of initiating programmed cell death. These death receptors initiate signal transduction pathways that culminate in caspase activation and apoptosis. A number of the intracellular molecules in these signaling pathways have been identified and characterized. In contrast to death receptors, other cell surface receptors appear to be capable of initiating signaling pathways that promote cell survival. The components of survival signal transduction are less well characterized. Recently a family of cytoplasmic proteins has been identified that appears to be capable of both negatively regulating apoptotic pathway(s) as well as inducing the expression of genes that promote cell survival. Members of this family of signal transduction molecules were first described because of their ability to bind to TNFRII and, therefore, were given the name TNF receptor-associated factors (TRAFs). Subsequent studies have demonstrated that TRAFs serve as adapter proteins for a wide variety of cell surface receptors and play important roles in regulating not only apoptosis but also stress responses. In this review we hope to provide an overview of current knowledge concerning the expression and function of this important family of proteins. Identification of the TRAF family Members of the recently described family of TRAF proteins are cytoplasmic adapter proteins that can interact directly with the intracellular domains of cell surface receptors. Among the receptors that have been shown to recruit TRAF proteins are members of the TNFR superfamily, the Epstein‐Barr virus protein LMP1, and the interleukin-1 receptor (IL-1R). To date, six distinct TRAF molecules have been identified in mammalian species (Fig. 1). TRAF1 and TRAF2 were cloned by biochemical