In my laboratory, we are investigating molecular mechanism of signal transduction that leads to gene activation. We are also interested in how specific signaling pathways are altered in inflammatory diseases and cancer. Currently, as a model system, we are investigating the signaling pathways involved in regulation of the Nuclear Factor kappa B family of transcription factors. The IkB kinase (IKK) complexes are the stimulus-dependent signaling components in the NF-kB pathways. The molecular mechanisms of IKK regulation and the ways various signaling pathways specifically activate them are not clear. To understand the specificity and diversity of signaling by IKK, our approach is to biochemically isolate and analyze endogenous signaling complexes containing IKK. To investigate the intra-and inter-molecular mechanisms of regulation, we have reconstituted IKK complexes in heterologous yeast. An important goal is to reconstitute a complete signaling pathway, from a receptor to activation of IKK, in the heterologous yeast system. Combining these strategies with structural, molecular, and cellular approaches in mammalian cell culture systems, the goal is to gain a detailed molecular understanding of the signal transduction mechanisms leading to NF-kB activation. By studying how these mechanisms are altered in human diseases, therapeutic strategies can be developed.