IκB kinase
The IκB kinase (IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation.[1]
| IkappaB kinase | |||||||||
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| Identifiers | |||||||||
| EC number | 2.7.11.10 | ||||||||
| CAS number | 159606-08-3 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor of nuclear factor kappa B) protein inactivates the NF-κB transcription factor by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.[2][3][4] Specifically, IKK phosphorylates the inhibitory IκBα protein.[5] This phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is now free, migrates into the nucleus and activates the expression of at least 150 genes; some of which are anti-apoptotic.
Catalyzed reaction
In enzymology, an IκB kinase (EC 2.7.11.10) is an enzyme that catalyzes the chemical reaction:
- ATP + IκB protein ADP + IκB phosphoprotein
Thus, the two substrates of this enzyme are ATP and IκB protein, whereas its two products are ADP and IκB phosphoprotein.
This enzyme belongs to the family of transferases, specifically those transferring a phosphate group to the sidechain oxygen atom of serine or threonine residues in proteins (protein-serine/threonine kinases). The systematic name of this enzyme class is ATP:[IκB protein] phosphotransferase.
Structure
The IκB kinase complex is composed of three subunits each encoded by a separate gene:
- IKK-α (also known as IKK1) (CHUK)
- IKK-β (also known as IKK2) (IKBKB)
- IKK-γ (also known as NEMO) (IKBKG)
The α- and β-subunits together are catalytically active whereas the γ-subunit serves a regulatory function.
The IKK-α and IKK-β kinase subunits are homologous in structure, composed of a kinase domain, as well as leucine zipper and helix-loop-helix dimerization domains, and a carboxy-terminal NEMO-binding domain (NBD).[6] Mutational studies have revealed the identity of the NBD amino acid sequence as leucine-aspartate-tryptophan-serine-tryptophan-leucine, encoded by residues 737-742 and 738-743 of IKK-α and IKK-β, respectively.[7] The regulatory IKK-γ subunit, or NEMO, is composed of two coiled coil domains, a leucine zipper dimerization domain, and a zinc finger-binding domain.[6] Specifically, the NH2-terminus of NEMO binds to the NBD sequences on IKK-α and IKK-β, leaving the rest of NEMO accessible for interacting with regulatory proteins.[7]
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Function
IκB kinase activity is essential for activation of members of the nuclear factor-kB (NF-κB) family of transcription factors, which play a fundamental role in lymphocyte immunoregulation.[6][8] Activation of the canonical, or classical, NF-κB pathway begins in response to stimulation by various pro-inflammatory stimuli, including lipopolysaccharide (LPS) expressed on the surface of pathogens, or 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.[5] 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.[8] 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.[9]
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.[5]
Deregulation and disease
Though functionally adaptive in response to inflammatory stimuli, deregulation of NF-κB signaling has been exploited in various disease states.[5][6][7][8][9][10] 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.[8][10] 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.[8][9]
Clinical significance
This enzyme participates in 15 pathways related to metabolism: MapK signaling, apoptosis, Toll-like receptor signaling, T-cell receptor signaling, B-cell receptor signaling, insulin signaling, adipokine signaling, Type 2 diabetes mellitus, epithelial cell signaling in helicobacter pylori, pancreatic cancer, prostate cancer, chronic myeloid leukemia, acute myeloid leukemia, and small cell lung cancer.
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[11] The small-molecule inhibitor of IKK-β SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.[11][12]
References
- Häcker H, Karin M (October 2006). "Regulation and function of IKK and IKK-related kinases". Sci. STKE. 2006 (357): re13. doi:10.1126/stke.3572006re13. PMID 17047224.
- Jacobs MD, Harrison SC (1998). "Structure of an IkappaBalpha/NF-kappaB complex". Cell. 95 (6): 749–58. doi:10.1016/S0092-8674(00)81698-0. PMID 9865693.
- Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (1997). "Identification and characterization of an IkappaB kinase". Cell. 90 (2): 373–83. doi:10.1016/S0092-8674(00)80344-X. PMID 9244310.
- Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A (1997). "IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation". Science. 278 (5339): 860–6. doi:10.1126/science.278.5339.860. PMID 9346484.
- Karin M (1999). "How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex". Oncogene. 18 (49): 6867–74. doi:10.1038/sj.onc.1203219. PMID 10602462.
- Ghosh S, Hayden M (November 2008). "New regulators of NF-κB in inflammation". Nat. Rev. Immunol. 8 (11): 837–48. doi:10.1038/nri2423. PMID 18927578.
- May MJ, D'acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (September 2000). "Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex". Science. 289 (5484): 1550–54. doi:10.1126/science.289.5484.1550. PMID 10968790.
- Strickland I, Ghosh S (November 2006). "Use of cell permeable NBD peptides for suppression of inflammation". Ann Rheum Dis. 65 (Suppl 3): iii75–iii82. doi:10.1136/ard.2006.058438. PMC 1798375. PMID 17038479.
- Jost PJ, Ruland J (April 2007). "Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications". Blood. 109 (7): 2700–7. doi:10.1182/blood-2006-07-025809. PMID 17119127.
- Tak PP, Firestein GS (January 2001). "NF-κB: a key role in inflammatory diseases". J. Clin. Invest. 107 (1): 7–11. doi:10.1172/JCI11830. PMC 198552. PMID 11134171.
- Llona-Minguez S, Baiget J, Mackay SP (2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.
- "SAR113945 published clinical trials".
Further reading
- Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (1997). "The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation". Cell. 91 (2): 243–52. doi:10.1016/S0092-8674(00)80406-7. PMID 9346241.
- Viatour P, Merville MP, Bours V, Chariot A (2005). "Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation". Trends Biochem. Sci. 30 (1): 43–52. doi:10.1016/j.tibs.2004.11.009. PMID 15653325.
External links
- I-kappa+B+Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)