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Mitogen-activated protein kinase kinase kinase 5
PDB rendering based on 2clq.
Available structures: 2clq
Symbol(s) MAP3K5; ASK1; MAPKKK5; MEKK5
External IDs OMIM: 602448 MGI: 1346876 Homologene: 38114
RNA expression pattern

More reference expression data

Human Mouse
Entrez 4217 26408
Ensembl ENSG00000197442 na
Uniprot Q99683 na
Refseq NM_005923 (mRNA)
NP_005914 (protein)
XM_001006040 (mRNA)
XP_001006040 (protein)
Location Chr 6: 136.92 - 137.16 Mb na
Pubmed search [1] [2]

Apoptosis signal-regulating kinase 1, ASK-1, is part of the mitogen-activated protein kinase (MAPK) cascade. In humans it is also known as "mitogen-activated protein kinase kinase kinase 5", abbreviated as "MAP3K5".

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. Phosphorylation of ASK-1 protein can lead to apoptosis or other cellular responses depending on the cell type. Northern blot analysis shows that ASK-1 transcript is abundantly expressed in human heart and pancreas. The ASK-1 (MAPKKK5) protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; ASK-1 does not activate MAPK/ERK.[1]

ASK-1 found in the inactive form, bound to reduced thioredoxin. When oxidized by a reactive oxygen species, Trx dissociates from ASK-1. The ASK-1, which is found as a homo-oligodimer, autophosphorylates and becomes an active MAP kinase kinase kinase.

ASK-1 contains 1,374 amino acids with all 11 kinase subdomains. It is located on chromosome 6 at locus 6q22.33.


  1. ^ Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5.

Further reading

  • Hayakawa T, Matsuzawa A, Noguchi T, Takeda K, Ichijo H (2006). "The ASK1-MAP kinase pathways in immune and stress responses". Microbes Infect. 8 (4): 1098-107. doi:10.1016/j.micinf.2005.12.001. PMID 16517200.
  • Nagai H, Noguchi T, Takeda K, Ichijo H (2007). "Pathophysiological roles of ASK1-MAP kinase signaling pathways.". J. Biochem. Mol. Biol. 40 (1): 1-6. PMID 17244475.
  • Wang XS, Diener K, Jannuzzi D, et al. (1997). "Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase.". J. Biol. Chem. 271 (49): 31607-11. PMID 8940179.
  • Ichijo H, Nishida E, Irie K, et al. (1997). "Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.". Science 275 (5296): 90-4. PMID 8974401.
  • Rampoldi L, Zimbello R, Bortoluzzi S, et al. (1998). "Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5.". Cytogenet. Cell Genet. 78 (3-4): 301-3. PMID 9465908.
  • Saitoh M, Nishitoh H, Fujii M, et al. (1998). "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.". EMBO J. 17 (9): 2596-606. doi:10.1093/emboj/17.9.2596. PMID 9564042.
  • Gotoh Y, Cooper JA (1998). "Reactive oxygen species- and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-alpha signal transduction.". J. Biol. Chem. 273 (28): 17477-82. PMID 9651337.
  • Chang HY, Nishitoh H, Yang X, et al. (1998). "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx.". Science 281 (5384): 1860-3. PMID 9743501.
  • Nishitoh H, Saitoh M, Mochida Y, et al. (1998). "ASK1 is essential for JNK/SAPK activation by TRAF2.". Mol. Cell 2 (3): 389-95. PMID 9774977.
  • Wang XS, Diener K, Tan TH, Yao Z (1999). "MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5.". Biochem. Biophys. Res. Commun. 253 (1): 33-7. doi:10.1006/bbrc.1998.9749. PMID 9875215.
  • Zhang L, Chen J, Fu H (1999). "Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins.". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8511-5. PMID 10411906.
  • Hoeflich KP, Yeh WC, Yao Z, et al. (1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1).". Oncogene 18 (42): 5814-20. doi:10.1038/sj.onc.1202975. PMID 10523862.
  • Takeda K, Hatai T, Hamazaki TS, et al. (2000). "Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells.". J. Biol. Chem. 275 (13): 9805-13. PMID 10734135.
  • Mochida Y, Takeda K, Saitoh M, et al. (2000). "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction.". J. Biol. Chem. 275 (42): 32747-52. doi:10.1074/jbc.M003042200. PMID 10921914.
  • Charette SJ, Lavoie JN, Lambert H, Landry J (2000). "Inhibition of Daxx-mediated apoptosis by heat shock protein 27.". Mol. Cell. Biol. 20 (20): 7602-12. PMID 11003656.
  • McDonald PH, Chow CW, Miller WE, et al. (2000). "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.". Science 290 (5496): 1574-7. PMID 11090355.
  • Ko YG, Kim EY, Kim T, et al. (2001). "Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.". J. Biol. Chem. 276 (8): 6030-6. doi:10.1074/jbc.M006189200. PMID 11096076.
  • Kim AH, Khursigara G, Sun X, et al. (2001). "Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1.". Mol. Cell. Biol. 21 (3): 893-901. doi:10.1128/MCB.21.3.893-901.2001. PMID 11154276.
  • Cho SG, Lee YH, Park HS, et al. (2001). "Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1.". J. Biol. Chem. 276 (16): 12749-55. doi:10.1074/jbc.M005561200. PMID 11278289.
  • Geleziunas R, Xu W, Takeda K, et al. (2001). "HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell.". Nature 410 (6830): 834-8. doi:10.1038/35071111. PMID 11298454.
  • Xu XN, Screaton G (2001). "HIV-1 Nef: negative effector of Fas?". Nat. Immunol. 2 (5): 384-5. doi:10.1038/87682. PMID 11323689.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "ASK-1". A list of authors is available in Wikipedia.
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