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). TRAF5 is a 558-amino acid protein. TRAF5 is implicated in NF-κ,B and c-Jun NH-terminal kinase/stress-activated protein kinase activation by members of the TNF receptor superfamily, including CD27, CD30, CD40, and lymphotoxin-beta receptor. Targeted disruption of TRAF5 gene causes defects in CD40-CD27 mediated lymhocyte activation.