ASK1

Mitogen-activated protein kinase kinase kinase 5
PDB rendering based on 2clq.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2CLQ​, 3VW6​, 4BF2​, 4BHN​, 4BIB​, 4BIC​, 4BID​, 4BIE​
Identifiers
Symbols	MAP3K5 ; ASK1; MAPKKK5; MEKK5
External IDs	OMIM: 602448 MGI: 1346876 HomoloGene: 38114 ChEMBL: 5285 GeneCards: MAP3K5 Gene
EC number	2.7.11.25
Gene ontology Molecular function • magnesium ion binding • protein kinase activity • MAP kinase kinase kinase activity • protein binding • ATP binding • protein kinase binding • protein phosphatase binding • protein homodimerization activity Cellular component • cytosol • protein kinase complex • IRE1-TRAF2-ASK1 complex Biological process • MAPK cascade • activation of MAPKK activity • response to ischemia • protein phosphorylation • JNK cascade • activation of JUN kinase activity • intrinsic apoptotic signaling pathway in response to oxidative stress • viral process • response to endoplasmic reticulum stress • p38MAPK cascade • positive regulation of apoptotic process • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • positive regulation of JUN kinase activity • innate immune response • positive regulation of myoblast differentiation • positive regulation of JNK cascade • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • cellular response to hydrogen peroxide • apoptotic signaling pathway • programmed necrotic cell death • positive regulation of neuron death • cellular response to reactive nitrogen species Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
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: 19.93 – 20.14 Mb
PubMed search

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase kinase 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, cardiovascular and neurodegenerative diseases.^[1]

MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33.^[2] 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.^[3]

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).^[4] 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.^[5] 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.^[6]

Interactions

ASK1 has been shown to interact with PP5:^[7]

• C-Raf,^[8]
• CDC25A,^[9]
• DAXX,^[10]
• DUSP19,^[11]
• EIF2AK2,^[12]
• GADD45B,^[13]
• HSPA1A,^[14]
• MAP2K6,^[7][15]
• MAP3K7^[16] and
• MAPK8IP3,^[17]
• PDCD6,^[18]
• PPP5C,^[7]
• RB1CC1,^[19]
• TRAF2,^[19][20]
• TRAF5,^[20][21] and
• TRAF6.^[16][20][21]

References

1. Hattori K, Naguro I, Runchel C, Ichijo H (2009). "The roles of ASK family proteins in stress responses and diseases". Cell Commun. Signal 7: 9. doi:10.1186/1478-811X-7-9. PMC 2685135. PMID 19389260.
2. Rampoldi L, Zimbello R, Bortoluzzi S, Tiso N, Valle G, Lanfranchi G, Danieli GA (1997). "Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5". Cytogenet. Cell Genet. 78 (3-4): 301–3. doi:10.1159/000134677. PMID 9465908.
3. "Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5".
4. Yoon KW, Cho JH, Lee JK, Kang YH, Chae JS, Kim YM, Kim J, Kim EK, Kim SE, Baik JH, Naik UP, Cho SG, Choi EJ (October 2009). "CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1". Proc. Natl. Acad. Sci. U.S.A. 106 (41): 17389–94. doi:10.1073/pnas.0812259106. PMC 2762684. PMID 19805025.
5. Noguchi T, Takeda K, Matsuzawa A, Saegusa K, Nakano H, Gohda J, Inoue J, Ichijo H (November 2005). "Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death". J. Biol. Chem. 280 (44): 37033–40. doi:10.1074/jbc.M506771200. PMID 16129676.
6. Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, Ichijo H (December 2007). "Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1". Mol. Cell. Biol. 27 (23): 8152–63. doi:10.1128/MCB.00227-07. PMC 2169188. PMID 17724081.
7. Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H (November 2001). "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress". EMBO J. 20 (21): 6028–36. doi:10.1093/emboj/20.21.6028. PMC 125685. PMID 11689443.
8. Chen J, Fujii K, Zhang L, Roberts T, Fu H (July 2001). "Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism". Proc. Natl. Acad. Sci. U.S.A. 98 (14): 7783–8. doi:10.1073/pnas.141224398. PMC 35419. PMID 11427728.
9. Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H (July 2001). "The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1". Mol. Cell. Biol. 21 (14): 4818–28. doi:10.1128/MCB.21.14.4818-4828.2001. PMC 87174. PMID 11416155.
10. 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. doi:10.1126/science.281.5384.1860. PMID 9743501.
11. Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M (June 2002). "Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway". J. Biol. Chem. 277 (26): 23919–26. doi:10.1074/jbc.M200838200. PMID 11959862.
12. Takizawa T, Tatematsu C, Nakanishi Y (Dec 2002). "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". Eur. J. Biochem. 269 (24): 6126–32. doi:10.1046/j.1432-1033.2002.03325.x. PMID 12473108.
13. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, Nguyen DU, Pham CG, Nelsbach AH, Melis T, De Smaele E, Tang WJ, D'Adamio L, Franzoso G (February 2004). "Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2". Nat. Cell Biol. 6 (2): 146–53. doi:10.1038/ncb1093. PMID 14743220.
14. Park HS, Cho SG, Kim CK, Hwang HS, Noh KT, Kim MS, Huh SH, Kim MJ, Ryoo K, Kim EK, Kang WJ, Lee JS, Seo JS, Ko YG, Kim S, Choi EJ (November 2002). "Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1". Mol. Cell. Biol. 22 (22): 7721–30. doi:10.1128/MCB.22.22.7721-7730.2002. PMC 134722. PMID 12391142.
15. Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, Houghton PJ (June 2003). "Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)". Mol. Cell 11 (6): 1491–501. doi:10.1016/S1097-2765(03)00180-1. PMID 12820963.
16. Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J, Matsumoto K, Ichijo H (October 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.
17. Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, Yoshioka K, Ichijo H (October 2002). "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade". J. Biol. Chem. 277 (43): 40703–9. doi:10.1074/jbc.M202004200. PMID 12189133.
18. Hwang IS, Jung YS, Kim E (October 2002). "Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation". FEBS Lett. 529 (2-3): 183–7. doi:10.1016/S0014-5793(02)03329-X. PMID 12372597.
19. Gan B, Peng X, Nagy T, Alcaraz A, Gu H, Guan JL (October 2006). "Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways". J. Cell Biol. 175 (1): 121–33. doi:10.1083/jcb.200604129. PMC 2064504. PMID 17015619.
20. Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H (September 1998). "ASK1 is essential for JNK/SAPK activation by TRAF2". Mol. Cell 2 (3): 389–95. doi:10.1016/S1097-2765(00)80283-X. PMID 9774977.
21. 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.

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. doi:10.5483/BMBRep.2007.40.1.001. PMID 17244475.
• Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, Zukowski M, Yao Z (1996). "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. doi:10.1074/jbc.271.49.31607. PMID 8940179.
• Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y (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.
• Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H (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. PMC 1170601. PMID 9564042.
• Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D (1998). "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx". Science 281 (5384): 1860–3. doi:10.1126/science.281.5384.1860. PMID 9743501.
• Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H (1998). "ASK1 is essential for JNK/SAPK activation by TRAF2". Mol. Cell 2 (3): 389–95. doi:10.1016/S1097-2765(00)80283-X. PMID 9774977.
• Wang XS, Diener K, Tan TH, Yao Z (1998). "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. doi:10.1073/pnas.96.15.8511. PMC 17547. PMID 10411906.
• Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (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, Nishitoh H, Saitoh M, Ichijo H (2000). "Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells". J. Biol. Chem. 275 (13): 9805–13. doi:10.1074/jbc.275.13.9805. PMID 10734135.
• 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. 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 (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, Franke TF, Chao MV (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. PMC 86680. PMID 11154276.
• Cho SG, Lee YH, Park HS, Ryoo K, Kang KW, Park J, Eom SJ, Kim MJ, Chang TS, Choi SY, Shim J, Kim Y, Dong MS, Lee MJ, Kim SG, Ichijo H, Choi EJ (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, Ichijo H, Greene WC (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.