A single NFκB system for both canonical and non-canonical signaling
- 23 November 2010
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cell Research
- Vol. 21 (1), 86-102
- https://doi.org/10.1038/cr.2010.161
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.Keywords
This publication has 112 references indexed in Scilit:
- Understanding the temporal codes of intra-cellular signalsCurrent Opinion in Genetics & Development, 2010
- A Ubiquitin Replacement Strategy in Human Cells Reveals Distinct Mechanisms of IKK Activation by TNFα and IL-1βMolecular Cell, 2009
- NF‐κB p52:RelB heterodimer recognizes two classes of κB sites with two distinct modesEMBO Reports, 2008
- UV as an Amplifier Rather Than Inducer of NF-κB ActivityMolecular Cell, 2008
- NF-κB dictates the degradation pathway of IκBαThe EMBO Journal, 2008
- Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple MyelomaCancer Cell, 2007
- Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple MyelomaCancer Cell, 2007
- A Fourth IκB Protein within the NF-κB Signaling ModuleCell, 2007
- Activation of IKK by TNFα Requires Site-Specific Ubiquitination of RIP1 and Polyubiquitin Binding by NEMOMolecular Cell, 2006
- Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin ChainCell, 2000