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TRAF‐Mediated TNFR‐Family Signaling

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Abstract

The tumor necrosis factor (TNF) superfamily consists of a wide variety of cell?bound and secreted proteins that regulate numerous cellular processes. In particular, TNF?family proteins regulate the proliferation and death of tumor cells, as well as activated immune cells. This overview discusses the mammalian TNF receptor?associated factors (TRAFs), of which TRAF1, 2, 3, 5, and 6 have been shown to interact directly or indirectly with members of the TNF receptor superfamily. Structural features of TRAF proteins are described along with a discussion of TRAF?interacting proteins and the signaling pathways activated by the TRAF proteins. Finally, we examine the phenotypes observed in TRAF?knockout mice. Curr. Protoc. Immunol. 87:11.9D.1?11.9D.19. © 2009 by John Wiley & Sons, Inc.

Keywords: TNF family; TNFR family; IL?1R/TLR; TRAF proteins; signal transduction; inflammation

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TNF and TNFR Superfamilies
Activated Receptors
TRAF Proteins
Structural Features of TRAF Proteins
TRAF‐Interacting Proteins
Signaling Pathways Activated by TRAF Proteins
TRAF Knockout Mice
Literature Cited
Figures
Tables

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Figure 11.9.1 Domain organization of mammalian tumor‐necrosis factor receptor (TNFR)‐associated factors (TRAFs). The TRAF family consists of seven proteins. Each TRAF, except TRAF1, has a RING‐finger domain (RING) with an associated E3 ligase activity, and a zinc‐finger motif (Zn). The C‐terminal domain (TRAF‐C) is highly conserved among the TRAF proteins, except for TRAF7. This domain modulates homo‐ and heterodimerization of the TRAF proteins, as well as associations with various cell surface receptors. The coiled‐coil N‐terminal structure (TRAF‐N) is less conserved. Whereas TRAF1 and 3 do not activate any kinases, TRAF2, 5, and 6 serve as adaptors to link cell‐surface receptors to kinases. TRAF7 has seven WD40 domains instead of TRAF‐C. Using this motif, TRAF7 binds MEKK3, which phosphorylates the N‐terminal region of TRAF7.

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Figure 11.9.2 Signaling pathways activated by TNF. Soluble TNF‐α acts primarily through TNFR1, whereas membrane‐bound TNF‐α functions via TNFR2. TRAF1/2 associates with TNFR2 directly, and with TNFR1 through TRADD and RIP.

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Figure 11.9.3 TRAF6‐dependent signaling pathways. TNFR‐family members, such as TRANCE‐R and CD40, bind to TRAF6 and other TRAF proteins, activating various pathways including Src‐family kinases. IL‐1R and Toll‐like receptors are indirectly linked to TRAF6 through MyD88, Tollip, and IRAK.

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