the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1). Following immune cell stimulation, a signal transduction cascade leads to the activation of the IKK complex, an event characterized by the binding of NEMO to the homologous kinase subunits IKK-α and IKK-β. The IKK complex phosphorylates serine residues (S32 and S36) within the amino-terminal domain of inhibitor of NF-κB (IκBα) upon activation, consequently leading to its ubiquitination and subsequent degradation by the proteasome. Degradation of IκBα releases the prototypical p50-p65 dimer for translocation to the nucleus, where it binds to κB sites and directs NF-κB-dependent transcriptional activity. NF-κB target genes can be differentiated by their different functional roles within lymphocyte immunoregulation and include positive cell-cycle regulators, anti-apoptotic and survival factors, and pro-inflammatory genes. Collectively, activation of these immunoregulatory factors promotes lymphocyte proliferation, differentiation, growth, and survival. Regulation Activation of the IKK complex is dependent on phosphorylation of serine residues within the kinase domain of IKK-β, though IKK-α phosphorylation occurs concurrently in endogenous systems. Recruitment of IKK kinases by the regulatory domains of NEMO leads to the phosphorylation of two serine residues within the activation loop of IKK-β, moving the activation loop away from the catalytic pocket, thus allowing access to ATP and IκBα peptide substrates. Furthermore, the IKK complex is capable of undergoing trans-autophosphorylation, where the activated IKK-β kinase subunit phosphorylates its adjacent IKK-α subunit, as well as other inactive IKK complexes, thus resulting in high levels of IκB kinase activity. Following IKK-mediated phosphorylation of IκBα and the subsequent decrease in IκB abundance, the activated IKK kinase subunits undergo extensive carboxy-terminal autophosphorylation, reaching a low activity state that is further susceptible to complete inactivation by phosphatases once upstream inflammatory signaling diminishes. Deregulation and disease Though functionally adaptive in response to inflammatory stimuli, deregulation of NF-κB signaling has been exploited in various disease states. Increased NF-κB activity as a result of constitutive IKK-mediated phosphorylation of IκBα has been observed in the development of atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. Specifically, constitutive NF-κB activity promotes continuous inflammatory signaling at the molecular level that translates to chronic inflammation phenotypically. Furthermore, the ability of NF-κB to simultaneously suppress apoptosis and promote continuous lymphocyte growth and proliferation explains its intimate connection with many types of cancer. Clinical significance This enzyme participates in 15 pathways related to metabolism: MapK signaling, apoptosis, Toll-like receptor signaling, T-cell receptor signaling, B-cell