(a) Generic schema for the cytokine/adaptor/MAPK signaling paradigm. Cytokines, such as TNF-α, trigger oligomerization of their enzymatically inactive cognate receptors. The conformational change in the receptor complex following ligand binding facilitates recruitment of adaptor proteins. These adaptor proteins within the receptor complex interact directly or indirectly with upstream kinases (MAPKKK) permitting their activation with subsequent phosphorylation and activation of downstream kinases (MAPKK/MAPK). (b) Model of TNF-α signaling pathway through TRAF2/ASK1 employing the cytokine/adaptor/MAPK paradigm. Triggering of TNF-R1 leads to recruitment of the adaptor TRAF2, and concomitant activation of an unknown phosphatase via a mechanism yet to be identified. TRAF2 mediates the association of ASK1 with the newly identified Ras-GAP AIP1, which facilitates the release of ASK1 from its endogenous inhibitor 14-3-3. Disruption of the ASK1/14-3-3 complex and de-phosphorylation of ASK1 by the unknown phosphatase result in the activation of ASK1. ASK1, in turn, activates JNK via an MKK4- or MKK6-dependent pathway. Activation of JNK positively regulates the apoptotic machinery by transcription-dependent (i.e., activation of the transcription factor AP-1) and transcription-independent (i.e., phosphorylation and activation of proapototic Bcl-2 proteins Bim and Bmf) mechanisms. P, phosphate.