MADD, A NOVEL DEATH DOMAIN PROTEIN THAT INTERACTS WITH THE TYPE-1 TUMOR-NECROSIS-FACTOR RECEPTOR AND ACTIVATES MITOGEN-ACTIVATED PROTEIN-KINASE

The death domain of the type 1 tumor necrosis factor receptor (TNFR1) mediates interactions with several proteins involved in signaling the downstream effects of TNF. We have used the yeast interaction trap to isolate a protein, MADD, that associates with the death domain of TNFR 1 through its own C-terminal death domain. MADD interacts with TNFR1 r esidues that are critical for signal generation and coimmunoprecipitat es with TNFR1, implicating MADD as a component of the TNFR1 signaling complex. Importantly, we have found that overexpression of MADD activa tes the mitogen-activated protein (MAP) kinase extracellular signal-re gulated kinase (ERK), and expression of the MADD death domain stimulat es both the ERK and c-JUN N-terminal kinase MAP kinases and induces th e phosphorylation of cytosolic phospholipase A(2). These data indicate that MADD links TNFR1 with MAP kinase activation and arachidonic acid release and provide further insight into the mechanisms by which TNF exerts its pleiotropic effects.