Regulation and function of IKK and IKK-related kinases.
Members of the nuclear factor kappa B (NF-kappaB) family of dimeric transcription factors (TFs) regulate expression of a large number of genes involved in immune responses, inflammation, cell survival, and cancer. NF-kappaB 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-kappaB TFs are bound to inhibitory IkappaB proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of IkappaB proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of IkappaB proteins liberates IkappaB-bound NF-kappaB TFs, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IKKalpha and IKKbeta, mediate phosphorylation of IkappaB proteins and represent a convergence point for most signal transduction pathways leading to NF-kappaB activation. Most of the IKKalpha and IKKbeta molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKKgamma or NEMO. Despite extensive sequence similarity, IKKalpha and IKKbeta have largely distinct functions, due to their different substrate specificities and modes of regulation. IKKbeta (and IKKgamma) are essential for rapid NF-kappaB activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor alpha (TNFalpha) or lipopolysaccharide (LPS). In contrast, IKKalpha functions in the activation of a specific form of NF-kappaB in response to a subset of TNF family members and may also serve to attenuate IKKbeta-driven NF-kappaB activation. Moreover, IKKalpha is involved in keratinocyte differentiation, but this function is independent of its kinase activity. Several years ago, two protein kinases, one called IKKepsilon or IKK-i and one variously named TBK1 (TANK-binding kinase), NAK (NF-kappaB-activated kinase), or T2K (TRAF2-associated kinase), were identified that exhibit structural similarity to IKKalpha 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.
Häcker
Hans
H
Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA. hans.haecker@stjude.org
Karin
Michael
M
D000818:Animals; D002460:Cell Line; D019281:Dimerization; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D020672:I-kappa B Proteins / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D007668:Kidney; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020672:I-kappa B Proteins; C491731:IKBKG protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C403191:TBK1 protein, human; D051550:I-kappa B Kinase