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Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including cytokines, growth factors and environmental stresses. A novel MAP kinase kinase kinase (MAPKKK) was recently identified and designated ASK1 (for apoptosis signal-regulating kinase 1) and MAPKKK5. ASK1 activated two different subgroups of MAPKK, MKK4 and MKK6, which in turn activated c-Jun N-terminal kinase (JNK) and p38 MAP kinase, respectively. ASK1/MAPKKK5 is activated by TNFR and Fas through the interaction with members of the TRAF family and Fas-associated protein Daxx. Overexpression of ASK1 induced apoptotic cell death, and a catalytically inactive form of ASK1 inhibited TNF-alpha-induced apoptosis. ASK1 is expressed in variety of human and mouse tissues.