title: A single NFκB system for both canonical and non-canonical signaling.
abstract: Two distinct nuclear factor κB (NFκB) signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune cell differentiation and maturation and secondary lymphoid organogenesis. The former is dependent on the IκB kinase adaptor molecule NEMO, the latter is independent of it. Here, we review the molecular mechanisms of regulation in each signaling axis and attempt to relate the apparent regulatory logic to the physiological function. Further, we review the recent evidence for extensive cross-regulation between these two signaling axes and summarize them in a wiring diagram. These observations suggest that NEMO-dependent and -independent signaling should be viewed within the context of a single NFκB signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. As in other regulatory biological systems, a systems approach including mathematical models that include quantitative and kinetic information will be necessary to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology.
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gillman Dr, La Jolla, CA 92093, USA.
authors.forename: Vincent Feng-Sheng
authors.initials: VF
authors.lastname: Shih
authors.forename: Rachel
authors.initials: R
authors.lastname: Tsui
authors.forename: Andrew
authors.initials: A
authors.lastname: Caldwell
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D051550:I-kappa B Kinase