Multiple roles of the NF‐?B signaling pathway regulated by coupled negative feedback circuits

The NF‐ΚB signaling pathway can perform multiple functional roles depending on specific cellular environments and cell types. Even in the same cell clones, the pathway can show different kinetic and phenotypic properties. It is believed that the complex networks controlling the NF‐KB signaling pathway can generate these diverse and sometimes ambiguous phenomena. We noted, however, that the dynamics of NF‐KB signaling pathway is highly stochastic and that the NF‐ΚB signaling pathway contains multiple negative feedback circuits formed by IΚB isoform proteins, IΚBα and IΚBε in particular. Considering the topological similarity, their functional roles seem to be redundant, raising the question why different types of IΚB isoforms need to exist. From extensive stochastic simulations of the NF‐ΚB signaling pathway, we found that each IΚB isoform actually conducts a different regulatory role through its own negative feedback. Specifically, our data suggest that IΚBα controls the dynamic patterns of nuclear NF‐KB, while IΚBε induces cellular heterogeneity of the NF‐ΚB activities. These results may provide an answer to the question of how a single NF‐ΚB signaling pathway can perform multiple biological functions even in the same clonal populations.— Kim, D., Kolch, W., Cho, K.‐H. Multiple roles of the NF‐ΚB signaling pathway regulated by coupled negative feedback circuits. FASEB J. 23, 2796–2802 (2009). www.fasebj.org