ASK1

MAP3K5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CLQ, 3VW6, 4BF2, 4BHN, 4BIB, 4BIC, 4BID, 4BIE
Identifiers
Aliases	MAP3K5, ASK1, MAPKKK5, MEKK5, mitogen-activated protein kinase kinase kinase 5
External IDs	OMIM: 602448; MGI: 1346876; HomoloGene: 38114; GeneCards: MAP3K5; OMA:MAP3K5 - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6q23.3 Start 136,557,046 bp End 136,792,477 bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10|10 A3 Start 19,810,218 bp End 20,018,499 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell Brodmann area 23 decidua pancreatic ductal cell adrenal cortex left adrenal gland right adrenal gland left adrenal cortex right adrenal cortex dorsal motor nucleus of vagus nerve Top expressed in ciliary body cumulus cell pineal gland retinal pigment epithelium hair follicle granulocyte iris transitional epithelium of urinary bladder ascending aorta vestibular membrane of cochlear duct More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding protein homodimerization activity metal ion binding kinase activity protein binding protein phosphatase binding MAP kinase kinase kinase activity ATP binding protein kinase binding magnesium ion binding protein serine/threonine kinase activity protein domain specific binding identical protein binding Cellular component cytoplasm protein kinase complex endoplasmic reticulum IRE1-TRAF2-ASK1 complex cytosol external side of plasma membrane protein-containing complex Biological process intrinsic apoptotic signaling pathway in response to oxidative stress positive regulation of protein phosphorylation phosphorylation immune system process regulation of cell death positive regulation of neuron death positive regulation of JNK cascade response to endoplasmic reticulum stress cellular response to reactive nitrogen species MAPK cascade protein phosphorylation JNK cascade positive regulation of cysteine-type endopeptidase activity involved in apoptotic process intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress response to ischemia positive regulation of myoblast differentiation positive regulation of apoptotic process apoptotic signaling pathway p38MAPK cascade programmed necrotic cell death innate immune response viral process cellular response to hydrogen peroxide apoptotic process cellular response to tumor necrosis factor positive regulation of cardiac muscle cell apoptotic process positive regulation of p38MAPK cascade wound healing positive regulation of JUN kinase activity positive regulation of vascular associated smooth muscle cell proliferation endothelial cell apoptotic process cellular response to amino acid starvation positive regulation of transcription, DNA-templated stress-activated MAPK cascade Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4217 26408 Ensembl ENSG00000197442 ENSMUSG00000071369 UniProt Q99683 O35099 RefSeq (mRNA) NM_005923 NM_008580 RefSeq (protein) NP_005914 NP_032606 Location (UCSC) Chr 6: 136.56 – 136.79 Mb Chr 10: 19.81 – 20.02 Mb PubMed search
Wikidata
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Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33. and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains. Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.

Mechanism of activation

Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx) and calcium and integrin binding protein 1 (CIB1). Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator. TRAF2 and TRAF6 are then recruited to ASK1 to form a larger molecular mass complex. Subsequently, ASK1 forms homo-oligomeric interactions not only through the CCC, but also the NCC, which leads to full activation of ASK1 through autophosphorylation at threonine 845.

ASK1 gene transcription can be induced by inflammatory cytokines such as IL-1 and TNF-α through the activation of the NF-kb protein RelA. Interestingly, TNF-α is also able to stabilize the ASK1 protein through deubiquitination. Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as post-transcriptional.

Interactions

ASK1 has been shown to interact with:

• C-Raf,
• CDC25A,
• DAXX,
• DUSP19,
• EIF2AK2,
• GADD45B,
• HSPA1A,
• MAP2K6,
• MAP3K7 and
• MAPK8IP3,
• PDCD6,
• PPP5C,
• RB1CC1,
• TRAF2,
• TRAF5, and
• TRAF6.

External links

• Human MAP3K5 genome location and MAP3K5 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q99683 (Mitogen-activated protein kinase kinase kinase 5) at the PDBe-KB.

Further reading

• Hayakawa T, Matsuzawa A, Noguchi T, Takeda K, Ichijo H (April 2006). "The ASK1-MAP kinase pathways in immune and stress responses". Microbes and Infection. 8 (4): 1098–107. doi:10.1016/j.micinf.2005.12.001. PMID 16517200.
• Nagai H, Noguchi T, Takeda K, Ichijo H (January 2007). "Pathophysiological roles of ASK1-MAP kinase signaling pathways". Journal of Biochemistry and Molecular Biology. 40 (1): 1–6. doi:10.5483/BMBRep.2007.40.1.001. PMID 17244475.
• Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, et al. (December 1996). "Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase". The Journal of Biological Chemistry. 271 (49): 31607–11. doi:10.1074/jbc.271.49.31607. PMID 8940179.
• Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, et al. (January 1997). "Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways". Science. 275 (5296): 90–4. doi:10.1126/science.275.5296.90. PMID 8974401. S2CID 23981616.
• Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, et al. (May 1998). "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1". The EMBO Journal. 17 (9): 2596–606. doi:10.1093/emboj/17.9.2596. PMC 1170601. PMID 9564042.
• Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D (September 1998). "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx". Science. 281 (5384): 1860–3. Bibcode:1998Sci...281.1860C. doi:10.1126/science.281.5384.1860. PMID 9743501.
• Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, et al. (September 1998). "ASK1 is essential for JNK/SAPK activation by TRAF2". Molecular Cell. 2 (3): 389–95. doi:10.1016/S1097-2765(00)80283-X. PMID 9774977.
• Wang XS, Diener K, Tan TH, Yao Z (December 1998). "MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5". Biochemical and Biophysical Research Communications. 253 (1): 33–7. doi:10.1006/bbrc.1998.9749. PMID 9875215.
• Zhang L, Chen J, Fu H (July 1999). "Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins". Proceedings of the National Academy of Sciences of the United States of America. 96 (15): 8511–5. Bibcode:1999PNAS...96.8511Z. doi:10.1073/pnas.96.15.8511. PMC 17547. PMID 10411906.
• Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (October 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. S2CID 12132452.
• Takeda K, Hatai T, Hamazaki TS, Nishitoh H, Saitoh M, Ichijo H (March 2000). "Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells". The Journal of Biological Chemistry. 275 (13): 9805–13. doi:10.1074/jbc.275.13.9805. PMID 10734135.
• Charette SJ, Lavoie JN, Lambert H, Landry J (October 2000). "Inhibition of Daxx-mediated apoptosis by heat shock protein 27". Molecular and Cellular Biology. 20 (20): 7602–12. doi:10.1128/MCB.20.20.7602-7612.2000. PMC 86317. PMID 11003656.
• Ko YG, Kim EY, Kim T, Park H, Park HS, Choi EJ, Kim S (February 2001). "Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1". The Journal of Biological Chemistry. 276 (8): 6030–6. doi:10.1074/jbc.M006189200. PMID 11096076.
• Kim AH, Khursigara G, Sun X, Franke TF, Chao MV (February 2001). "Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1". Molecular and Cellular Biology. 21 (3): 893–901. doi:10.1128/MCB.21.3.893-901.2001. PMC 86680. PMID 11154276.
• Cho SG, Lee YH, Park HS, Ryoo K, Kang KW, Park J, et al. (April 2001). "Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1". The Journal of Biological Chemistry. 276 (16): 12749–55. doi:10.1074/jbc.M005561200. PMID 11278289.
• Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC (April 2001). "HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell". Nature. 410 (6830): 834–8. Bibcode:2001Natur.410..834G. doi:10.1038/35071111. PMID 11298454. S2CID 4414424.