Tumor necrosis factor (TNF) induced signaling is mediated through association of TNF receptor (TNFR) with adaptor proteins, such as TNF receptor associated proteins (TRAFs). TRAFs form a family of cytoplasmic adapter proteins that mediate signal transduction from many members of the TNF-receptor superfamily (e.g. RANK, CD30, CD40, etc.) and the interleukin-1 receptor. The carboxy-terminal region of TRAFs is required for self-association and interaction with receptor cytoplasmic domains following ligand-induced oligomerization. Recent molecular cloning studies have lead to identification of six TRAFs (TRAF1-TRAF6) (1-4). Recently it has been shown that TRANCE/OPGL activates the antiapoptotic serine/threonine kinase Akt/PKB through a signaling complex involving c-Src and TRAF6 (5). Mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function (6). Like TRAF2 and TRAF3, TRAF6 is also essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling. RANK (TRANCE receptor) interacts with various TRAFs through distinct motifs and activates NF-kB via a novel TRAF6 interaction motif, which then activates NIK, thus leading to NF-kB activation (7). Over-expression of TRAF6 activates JNK, p38, or IKK in the absence of extracellular stimulation.
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