Review articleThe TNF-receptor-associated factor family: Scaffold molecules for cytokine receptors, kinases and their regulators
Section snippets
TRAF molecules, a phylogenetically conserved family of proteins
The first two name-giving members of the TNF-receptor-associated factor (TRAF) family were identified due to their association with the cytoplasmic tail of TNF-R2 and consequently designated as TRAF1 and TRAF2 [1]. While the cytoplasmic part of TNF-R2 directly interacts with TRAF2, TRAF1 is indirectly recruited to this receptor via interaction with TRAF2 [1]. Sequence comparison of TRAF1 and TRAF2 led to the identification of a conserved C-terminal domain within these molecules, designated as
Structure of TRAF molecules
The TD can be divided into a unique and highly homologous C-terminal subdomain (TRAF-C) and a less conserved N-terminal subdomain (TRAF-N). The latter subdomain was predicted to form a coiled-coil structure [1], [11]. It became clear early on that TDs bind to various members of the TNF receptor and IL-1R/Toll receptor family and are essential for the formation of TRAF homo- and heterotrimers, whereas the N-terminal part of the TRAF molecule is essential for signalling. Accordingly, N-terminally
Regulation of the expression of TRAF family members
The expression patterns of the various TRAF protein family members are strikingly different, indicating independent and cell type-specific regulation of each TRAF protein. TRAF2 [1], [31], TRAF3 [32] and TRAF6 [33] are ubiquitously expressed, whereas TRAF1, TRAF4 and TRAF5 show more restricted expression patterns. TRAF1 expression appears to be restricted to tonsils, spleen, testis and lung [1], [32] but can be drastically induced by selected stimuli (see below). The TRAF5 mRNA is highly
TRAF molecules interact with a variety of other proteins
For all TRAF family members, a variety of interacting proteins has been described. Most of these TRAF binding proteins interact with a defined subset of the TRAF protein family, but some of them are also specific for a single TRAF protein. About 40 interaction partners of TRAF proteins have been described in recent years. However, function and importance of these interactions are, in many cases, still elusive. Based on their overall function, the TRAF binding proteins can be classified into (1)
TRAF molecules are involved in activation and regulation of kinase signalling pathways
The most prominent signalling pathways triggered by stimulation of members of the TNF receptor family and the IL-1R/Toll receptor family are those leading to cell death, NF-κB activation and JNK stimulation. TRAF proteins seem not to be involved in transducing apoptotic effects with the exception of TRAF3, which appears to be involved in LTβ-R-induced apoptosis [96]. However, in all cases investigated so far, one or more members of the TRAF protein family are involved in NF-κB and JNK
TRANCE/RANK-L-induced activation of the Akt/PKB pathway
TRAF-dependent activation of JNK and NF-κB has been regularly found for members of the TNF receptor family and the IL-1R/Toll receptor family. In particular, this is also correct for RANK, a member of the TNF receptor family with a major role in the regulation of dendritic cell activation and osteoclastogenesis [123], [124], [125]. In accordance with these data, TRAF6 knockout mice have impaired osteoclast function leading to osteopetrosis, defects in bone remodeling and tooth eruption [119].
Conclusion
Beginning with the signal transduction pathways of TNF-R2, the TRAF story began in 1994 and has continuously expanded since then. No end to this process is in sight, and it is already clear that TRAF proteins are involved in multiple signalling pathways. The high number of TRAF interacting proteins points towards a tightly linked network of a variety of signalling molecules and effectors. TRAFs may therefore be capable of fine tuning many cellular responses, in particular, decisions between
Acknowledgements
We thank K. Pfizenmaier for helpful discussions and critical review of this manuscript. This work was supported by Deutsche Forschungsgemeinschaft Grant Wa 1025/3-1 and Sonderforschungsbereich 495.
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