TheIκB kinase (IkappaB kinase orIKK) is anenzyme complex that is involved in propagating the cellular response toinflammation,[1] specifically the regulation of lymphocytes.
The IκB kinase enzyme complex is part of the upstreamNF-κBsignal transduction cascade. TheIκBα (inhibitor of nuclear factor kappa B) protein inactivates the NF-κBtranscription factor by masking thenuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.[2][3][4] Specifically, IKKphosphorylates 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.
Inenzymology, an IκB kinase (EC2.7.11.10) is anenzyme thatcatalyzes thechemical reaction:
Thus, the twosubstrates of this enzyme areATP andIκB protein, whereas its twoproducts areADP and IκB phosphoprotein.
This enzyme belongs to the family oftransferases, specifically those transferring a phosphate group to the sidechainoxygen atom ofserine orthreonine residues inproteins (protein-serine/threonine kinases). Thesystematic name of this enzyme class is ATP:[IκB protein] phosphotransferase.
The IκB kinase complex is composed of three subunits each encoded by a separate gene:
The α- and β-subunits together are catalytically active whereas the γ-subunit serves a regulatory function.
The IKK-α and IKK-βkinase subunits are homologous in structure, composed of a kinase domain, as well asleucine zipper andhelix-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 twocoiled coil domains, a leucine zipper dimerization domain, and azinc 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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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, includinglipopolysaccharide (LPS) expressed on the surface of pathogens, or the release of pro-inflammatorycytokines such astumor necrosis factor (TNF) orinterleukin-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 phosphorylatesserine residues (S32 and S36) within the amino-terminal domain of inhibitor of NF-κB (IκBα) upon activation, consequently leading to itsubiquitination and subsequent degradation by theproteasome.[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]
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 theactivation 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-terminalautophosphorylation, reaching a low activity state that is further susceptible to complete inactivation byphosphatases once upstream inflammatory signaling diminishes.[5]
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 ofatherosclerosis,asthma,rheumatoid arthritis,inflammatory bowel diseases, andmultiple 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]
This enzyme participates in 15 pathways related tometabolism: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 inhelicobacter pylori,pancreatic cancer,prostate cancer,chronic myeloid leukemia,acute myeloid leukemia, andsmall cell lung cancer.
Inhibition of IκB kinase (IKK) and IKK-related kinases,IKBKE (IKKε) andTANK-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]
