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Mitogen-activated protein kinase kinase kinase 5
PBB Protein MAP3K5 image.jpg
PDB rendering based on 2clq.
Available structures
PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB
Symbols MAP3K5 ; ASK1; MAPKKK5; MEKK5
External IDs Template:OMIM5 Template:MGI HomoloGene38114
RNA expression pattern
PBB GE MAP3K5 203837 at tn.png
PBB GE MAP3K5 203836 s at tn.png
More reference expression data
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a

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.

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