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Sci. STKE, 17 October 2006
Vol. 2006, Issue 357, p. re13
[DOI: 10.1126/stke.3572006re13]

REVIEWS

Regulation and Function of IKK and IKK-Related Kinases

Hans Häcker1* and Michael Karin2

1Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
2Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Abstract: Members of the nuclear factor kappa B (NF-{kappa}B) family of dimeric transcription factors (TFs) regulate expression of a large number of genes involved in immune responses, inflammation, cell survival, and cancer. NF-{kappa}B TFs are rapidly activated in response to various stimuli, including cytokines, infectious agents, and radiation-induced DNA double-strand breaks. In nonstimulated cells, some NF-{kappa}B TFs are bound to inhibitory I{kappa}B proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of I{kappa}B proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of I{kappa}B proteins liberates I{kappa}B-bound NF-{kappa}B TFs, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IKK{alpha} and IKKbeta, mediate phosphorylation of I{kappa}B proteins and represent a convergence point for most signal transduction pathways leading to NF-{kappa}B activation. Most of the IKK{alpha} and IKKbeta molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKK{gamma} or NEMO. Despite extensive sequence similarity, IKK{alpha} and IKKbeta have largely distinct functions, due to their different substrate specificities and modes of regulation. IKKbeta (and IKK{gamma}) are essential for rapid NF-{kappa}B activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor {alpha} (TNF{alpha}) or lipopolysaccharide (LPS). In contrast, IKK{alpha} functions in the activation of a specific form of NF-{kappa}B in response to a subset of TNF family members and may also serve to attenuate IKKbeta-driven NF-{kappa}B activation. Moreover, IKK{alpha} is involved in keratinocyte differentiation, but this function is independent of its kinase activity. Several years ago, two protein kinases, one called IKK{varepsilon} or IKK-i and one variously named TBK1 (TANK-binding kinase), NAK (NF-{kappa}B–activated kinase), or T2K (TRAF2-associated kinase), were identified that exhibit structural similarity to IKK{alpha} and IKKbeta. These protein kinases are important for the activation of interferon response factor 3 (IRF3) and IRF7, TFs that play key roles in the induction of type I interferon (IFN-I). Together, the IKKs and IKK-related kinases are instrumental for activation of the host defense system. This Review focuses on the functions of IKK and IKK-related kinases and the molecular mechanisms that regulate their activities.

*Corresponding author. E-mail, hans.haecker{at}stjude.org

Citation: H. Häcker, M. Karin, Regulation and Function of IKK and IKK-Related Kinases. Sci. STKE 2006, re13 (2006).

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