View source for IκB kinase

{{cs1 config|name-list-style=vanc}}
{{Short description|Class of enzymes}}
{{infobox enzyme
| Name       = IkappaB kinase
| EC_number  = 2.7.11.10
| CAS_number = 159606-08-3
| GO_code    = 0008384
| image      =
| width      = 
| caption    =  
}}
The '''IκB kinase''' ('''IkappaB kinase''' or '''IKK''') is an [[enzyme]] complex that is involved in propagating the cellular response to [[inflammation]],<ref name="pmid17047224">{{Cite journal|vauthors = Häcker H, Karin M | title = Regulation and function of IKK and IKK-related kinases | journal = Sci. STKE | volume = 2006 | issue = 357 | pages = re13 |date=October 2006 | pmid = 17047224 | doi = 10.1126/stke.3572006re13 | s2cid = 19617181 }}</ref> specifically the regulation of lymphocytes.

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 signal]]s (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.<ref name="pmid9865693">{{Cite journal|vauthors=Jacobs MD, Harrison SC | title = Structure of an IkappaBalpha/NF-kappaB complex | journal = Cell | volume = 95 | issue = 6 | pages = 749–58 | year = 1998 | pmid = 9865693 | doi = 10.1016/S0092-8674(00)81698-0 | s2cid = 7003353 | doi-access = free }}</ref><ref name="pmid9244310">{{Cite journal|vauthors = Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M | title = Identification and characterization of an IkappaB kinase | journal = Cell | volume = 90 | issue = 2 | pages = 373–83 | year = 1997 | pmid = 9244310 | doi = 10.1016/S0092-8674(00)80344-X | s2cid = 16217708 | doi-access = free }}</ref><ref name="pmid9346484">{{Cite journal|vauthors = Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A | title = IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation | journal = Science | volume = 278 | issue = 5339 | pages = 860–6 | year = 1997 | pmid = 9346484 | doi = 10.1126/science.278.5339.860 | bibcode = 1997Sci...278..860M }}</ref>  Specifically, IKK [[phosphorylation|phosphorylates]] the inhibitory IκBα protein.<ref name="pmid10602462">{{Cite journal| author = Karin M | title = How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex | journal = Oncogene | volume = 18 | issue = 49 | pages = 6867–74 | year = 1999 | pmid = 10602462 | doi = 10.1038/sj.onc.1203219 | s2cid = 27754040 | doi-access =  }}</ref> 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 number|2.7.11.10}}) is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]:

:ATP + IκB protein <math>\rightleftharpoons</math> ADP + IκB phosphoprotein

Thus, the two [[substrate (biochemistry)|substrates]] of this enzyme are [[adenosine triphosphate|ATP]] and [[IκBα|IκB protein]], whereas its two [[product (chemistry)|products]] are [[adenosine diphosphate|ADP]] and IκB phosphoprotein.

This enzyme belongs to the family of [[transferase]]s, specifically those transferring a phosphate group to the sidechain [[oxygen]] atom of [[serine]] or [[threonine]] residues in [[protein]]s ([[protein-serine/threonine kinase]]s). The [[List of enzymes|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 [[CHUK|IKK1]]) ({{gene|CHUK}})
* IKK-β (also known as [[IKK2]]) ({{gene|IKBKB}})
* IKK-γ (also known as [[IKBKG|NEMO]]) ({{gene|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).<ref name="pmid18927578">{{Cite journal|vauthors= Ghosh S, Hayden M | title = New regulators of NF-κB in inflammation | journal = Nat. Rev. Immunol. | volume =8 | issue = 11 | pages = 837–48  | date=November 2008 | pmid = 18927578 | doi = 10.1038/nri2423 | s2cid = 31421212 }}</ref> 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.<ref name="pmid10968790">{{Cite journal| vauthors = May MJ, D'acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S | title = Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex | journal = Science | volume = 289 | issue = 5484 | pages = 1550–54 | date = September 2000 | pmid = 10968790 | doi = 10.1126/science.289.5484.1550 | bibcode = 2000Sci...289.1550M }}</ref> 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.<ref name="pmid18927578"/> 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.<ref name="pmid10968790"/>

{|
|- valign="top"
|{{infobox protein
| Name = [[CHUK|conserved helix-loop-helix ubiquitous kinase]]
| caption =
| image =
| width =
| HGNCid = 1974
| Symbol = CHUK
| AltSymbols = IKK-alpha, IKK1, TCF16
| EntrezGene = 1147
| OMIM = 600664
| RefSeq = NM_001278
| UniProt = O15111
| PDB =
| ECnumber = 2.7.11.10
| Chromosome = 10
| Arm = q
| Band = 24
| LocusSupplementaryData = -q25
}}
|{{infobox protein
| Name = [[IKK2|inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta]]
| caption =
| image =
| width =
| HGNCid = 5960
| Symbol = IKBKB
| AltSymbols = IKK-beta, IKK2
| EntrezGene = 3551
| OMIM = 603258
| RefSeq = NM_001556
| UniProt = O14920
| PDB =
| ECnumber = 2.7.11.10
| Chromosome = 8
| Arm = p
| Band = 11.2
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[IKBKG|inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma]]
| caption =
| image =
| width =
| HGNCid = 5961
| Symbol = IKBKG
| AltSymbols = IKK-gamma, NEMO, IP2, IP1
| EntrezGene = 8517
| OMIM = 300248
| RefSeq = NM_003639
| UniProt = Q9Y6K9
| PDB =
| ECnumber =
| Chromosome = X
| Arm = q
| Band = 28
| LocusSupplementaryData =
}}
|}

==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.<ref name="pmid18927578"/><ref name="pmid17038479">{{Cite journal|vauthors=Strickland I, Ghosh S | title = Use of cell permeable NBD peptides for suppression of inflammation | journal = Ann Rheum Dis | volume =65 | issue = Suppl 3 | pages = iii75–iii82 | date=November 2006 | pmid = 17038479 | doi = 10.1136/ard.2006.058438 | pmc=1798375}}</ref> 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]].<ref name="pmid10602462"/> 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.<ref name="pmid17038479"/> 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.<ref name="pmid17119127">{{Cite journal|vauthors=Jost PJ, Ruland J | title = Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications | journal = Blood | volume =109 | issue = 7 | pages = 2700–7 | date=April 2007 | pmid = 17119127 | doi = 10.1182/blood-2006-07-025809 | doi-access = free }}</ref>

==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.<ref name="pmid10602462"/>

==Deregulation and disease==

Though functionally adaptive in response to inflammatory stimuli, deregulation of NF-κB signaling has been exploited in various disease states.<ref name="pmid10602462"/><ref name="pmid18927578"/><ref name="pmid10968790"/><ref name="pmid17038479"/><ref name="pmid17119127"/><ref name="pmid11134171">{{Cite journal|vauthors=Tak PP, Firestein GS | title = NF-κB: a key role in inflammatory diseases | journal = J. Clin. Invest. | volume = 107 | issue = 1 | pages = 7–11 | date=January 2001 | pmid = 11134171 | doi = 10.1172/JCI11830 | pmc=198552}}</ref> 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]].<ref name="pmid17038479"/><ref name="pmid11134171"/> 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.<ref name="pmid17038479"/><ref name="pmid17119127"/>

== Clinical significance ==
This enzyme participates in 15 pathways related to [[metabolism]]: [[MAPK/ERK pathway|MapK signaling]], [[apoptosis]], [[Toll-like receptor#Signaling|Toll-like receptor signaling]], [[T-cell receptor]] signaling, [[B-cell receptor]] signaling, [[insulin#Signal transduction|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.<ref name="pmid24237125">{{cite journal |vauthors=Llona-Minguez S, Baiget J, Mackay SP | year = 2013 | title = Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases | journal = Pharm. Pat. Anal. | volume = 2 | pages = 481–498  | pmid = 24237125 | doi = 10.4155/ppa.13.31 | issue = 4 }}</ref> The small-molecule inhibitor of IKK-β SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.<ref name="pmid24237125"/><ref>{{cite web|url=http://clinicaltrials.gov/ct2/results?term=SAR113945&Search=Search|title= SAR113945 published clinical trials}}</ref>

==References==
{{Reflist|2}}

== Further reading ==
{{refbegin}}
* {{cite journal |vauthors=Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M | year = 1997 | title = The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation | journal = Cell  | volume = 91 | pages = 243&ndash;52  | pmid = 9346241 | doi = 10.1016/S0092-8674(00)80406-7 | issue = 2 | s2cid = 6399108 | doi-access = free }}
* {{cite journal |vauthors=Viatour P, Merville MP, Bours V, Chariot A | year = 2005 | title = Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation | journal = Trends Biochem. Sci.  | volume = 30 | pages = 43&ndash;52  | pmid = 15653325 | doi = 10.1016/j.tibs.2004.11.009 | issue = 1 | url = https://orbi.uliege.be/bitstream/2268/1280/1/21.%20Review%20phosphorylation%20NF-kB%20TIBS.pdf }}
{{refend}}

==External links==
* {{MeshName|I-kappa+B+Kinase}}

{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Ikappab Kinase}}
[[Category:EC 2.7.11]]
[[Category:Enzymes of unknown structure]]
[[Category:Protein complexes]]