IκB kinase

IkappaB kinase
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 / EGO
Search PMC articles PubMed articles NCBI proteins

The IκB kinase (IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation.^[1]

The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor of 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 $\rightleftharpoons$ 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.

conserved helix-loop-helix ubiquitous kinase Identifiers Symbol CHUK Alt. symbols IKK-alpha, IKK1, TCF16 Entrez 1147 HUGO 1974 OMIM 600664 RefSeq NM_001278 UniProt O15111 Other data EC number 2.7.11.10 Locus Chr. 10 q24-q25

inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta Identifiers Symbol IKBKB Alt. symbols IKK-beta, IKK2 Entrez 3551 HUGO 5960 OMIM 603258 RefSeq NM_001556 UniProt O14920 Other data EC number 2.7.11.10 Locus Chr. 8 p11.2

inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma Identifiers Symbol IKBKG Alt. symbols IKK-gamma, NEMO, IP2, IP1 Entrez 8517 HUGO 5961 OMIM 300248 RefSeq NM_003639 UniProt Q9Y6K9 Other data Locus Chr. X q28

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.^[6] The small-molecule inhibitor of IKK-β SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.^[6][7]

References

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Llona-Minguez S, Baiget J, Mackay S P, (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.
7. "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)