Figure 7.

Proposed model. Based on our findings, the following model is proposed for TNFα-induced TRAF2-mediated activation of diverse signaling pathways: first, upon TNFα treatment, TRAF2 is recruited to TNFR through TRADD where TRAF2, in turn, recruits upstream kinase(s) and activates the IKK signaling pathway; independently, TRAF2 undergoes Ubc13-dependent ubiquitination, which induces its translocation to the insoluble membrane rafts, where it is likely to recruit upstream kinases (e.g. MEKK1 and GCK). Although the complex assembled within the lipid rafts may suffice for the activation of JNK per se, further translocation of TRAF2 to insoluble cytoskeletal (or other cytosolic positioned) fraction occurs to bring JNK to necessary substrates (i.e. paxillin). It is also possible that localization within the insoluble portion serves to limit the duration of JNK activity. Neither ubiquitination, nor TRAF2 RING activity or translocation is required for the activation of p38 or IKK, indicating that the latter are subjected to alternate regulatory quos.