MAP kinase-activating death domain protein (MADD) was initially identified as the type 1 tumor necrosis factor receptor (TNFR1) associated protein though their death domains. Overexpression of MADD activates MAP kinases ERK and JNK and induces the phosphorylation of cytosolic phospholipase A2. MADD shares 98% identity with DENN (for differentially expressed in neoplastic vs. normal cells), which was recently identified as a substrate for c-jun N-terminal kinase 3 (JNK3). MADD has greater than 94% overall identity to a GDP/GTP exchange protein Rab3-GEP. MADD is 87% identical to KIAA0358, a brain protein of unknown function. Identification of MADD as a component of the TNFR1 signaling complex and the similarity between MADD and Rab3-GEP provides a connection between TNFR1 activation and downstream MAP kinase activity through a guanine-nucleotide exchange protein.