IκB kinase

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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

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] IKK specifically, 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[edit]

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[edit]

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.

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
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
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[edit]

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, adipocytokine 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[edit]

  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. ^ a b 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[edit]

  • 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[edit]