TRAFMediated TNFRFamily Signaling

TNF/TNFR SUPERFAMILIES

The tumor necrosis factor (TNF) superfa-mily consists of a wide variety of proteins, some cell-bound and others secreted, that regulate many cellular processes. In particular, TNF-family proteins regulate the life and death not only of tumor cells, but of activated cells of the immune system. They modulate the activation state of immune cells, and as we are increasingly becoming aware, they mediate the signals that these cells send to each other. TNF-family proteins have been implicated in areas outside of inflammation and immunity, including bone homeostasis, lymph node organogenesis, hair follicle development, and mammary gland development (Locksley et al., 2001).

TNF-family proteins mediate cellular effects by binding to their cognate cellular receptors, members of the TNF receptor (TNFR) superfamily (Ashkenazi and Dixit, 1998; Baker and Reddy, 1998; Wallach et al., 1999; Locksley et al., 2001). TNF-family proteins are expressed as type II transmembrane proteins that form trimers and which may interact with their cognate receptors as cell-bound or soluble forms (Idriss and Naismith, 2000). TNFR-fam-ily proteins are type I transmembrane proteins with conserved cysteine-rich domains (CRDs) that typically consist of three conserved disul-fide bridges (Smith et al., 1994). These domains form elongated receptor chains that intercalate with protomers of ligand trimers (Banner et al., 1993). It has been suggested that encounter with a ligand trimer induces the trimerization of a receptor, which leads to intracellular signaling, although recently it has been shown that TNFR proteins self-assemble in the absence of ligand, undergoing conformational changes upon ligand engagement that lead to signaling (Chan et al., 2000). While the extracellular ligand-binding domains of TNFR proteins are similar, there are three divergent subgroups of TNFR proteins that can be classified by motifs (or lack thereof) in their cytoplasmic tails: death receptors, decoy receptors, and activating receptors. Since TNFR proteins appear to lack intrinsic enzymatic activity, their intracellular signals are mediated by cytoplasmic adaptor proteins. Table 11.9D.1 lists known TNFR-family proteins by standardized TNFR-super-family nomenclature (TNFRSF), their ligands, intracellular adaptor molecules with which they interact, and known physiological functions (adapted from Locksley et al., 2001).

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