ASK1 explained

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.^{[1] [2]}

MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33.^[3] 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.^[4]

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).^[5] 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.^[6] 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.^[7]

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.^[8] 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,^[9]
• CDC25A,^[10]
• DAXX,^[11]
• DUSP19,^[12]
• EIF2AK2,^[13]
• GADD45B,^[14]
• HSPA1A,^[15]
• MAP2K6,^[16]
• MAP3K7 and
• MAPK8IP3,^[17]
• PDCD6,^[18]
• PPP5C,^[19]
• RB1CC1,^[20]
• TRAF2,^{[20] [21]}
• TRAF5,^[21] and
• TRAF6.^{[22] [21] [23]}

Further reading

• Hayakawa T, Matsuzawa A, Noguchi T, Takeda K, Ichijo H . The ASK1-MAP kinase pathways in immune and stress responses . Microbes and Infection . 8 . 4 . 1098–107 . April 2006 . 16517200 . 10.1016/j.micinf.2005.12.001 . free .
• Nagai H, Noguchi T, Takeda K, Ichijo H . Pathophysiological roles of ASK1-MAP kinase signaling pathways . Journal of Biochemistry and Molecular Biology . 40 . 1 . 1–6 . January 2007 . 17244475 . 10.5483/BMBRep.2007.40.1.001 . free .
• Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, Zukowski M, Yao Z . 6 . 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 . December 1996 . 8940179 . 10.1074/jbc.271.49.31607 . free .
• Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y . 6 . Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways . Science . 275 . 5296 . 90–4 . January 1997 . 8974401 . 10.1126/science.275.5296.90 . 23981616 .
• Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H . 6 . Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1 . The EMBO Journal . 17 . 9 . 2596–606 . May 1998 . 9564042 . 1170601 . 10.1093/emboj/17.9.2596 .
• Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D . Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx . Science . 281 . 5384 . 1860–3 . September 1998 . 9743501 . 10.1126/science.281.5384.1860 . 1998Sci...281.1860C .
• Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H . 6 . ASK1 is essential for JNK/SAPK activation by TRAF2 . Molecular Cell . 2 . 3 . 389–95 . September 1998 . 9774977 . 10.1016/S1097-2765(00)80283-X . free .
• Wang XS, Diener K, Tan TH, Yao Z . MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5 . Biochemical and Biophysical Research Communications . 253 . 1 . 33–7 . December 1998 . 9875215 . 10.1006/bbrc.1998.9749 .
• Zhang L, Chen J, Fu H . 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 . July 1999 . 10411906 . 17547 . 10.1073/pnas.96.15.8511 . 1999PNAS...96.8511Z . free .
• Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR . Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1) . Oncogene . 18 . 42 . 5814–20 . October 1999 . 10523862 . 10.1038/sj.onc.1202975 . 12132452 .
• Takeda K, Hatai T, Hamazaki TS, Nishitoh H, Saitoh M, Ichijo H . Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells . The Journal of Biological Chemistry . 275 . 13 . 9805–13 . March 2000 . 10734135 . 10.1074/jbc.275.13.9805 . free .
• Charette SJ, Lavoie JN, Lambert H, Landry J . Inhibition of Daxx-mediated apoptosis by heat shock protein 27 . Molecular and Cellular Biology . 20 . 20 . 7602–12 . October 2000 . 11003656 . 86317 . 10.1128/MCB.20.20.7602-7612.2000 .
• Ko YG, Kim EY, Kim T, Park H, Park HS, Choi EJ, Kim S . Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1 . The Journal of Biological Chemistry . 276 . 8 . 6030–6 . February 2001 . 11096076 . 10.1074/jbc.M006189200 . free .
• Kim AH, Khursigara G, Sun X, Franke TF, Chao MV . Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 . Molecular and Cellular Biology . 21 . 3 . 893–901 . February 2001 . 11154276 . 86680 . 10.1128/MCB.21.3.893-901.2001 .
• 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 . 6 . 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 . April 2001 . 11278289 . 10.1074/jbc.M005561200 . free .
• Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC . HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell . Nature . 410 . 6830 . 834–8 . April 2001 . 11298454 . 10.1038/35071111 . 2001Natur.410..834G . 4414424 .

Notes and References

1. Hattori K, Naguro I, Runchel C, Ichijo H . The roles of ASK family proteins in stress responses and diseases . Cell Communication and Signaling . 7 . 9 . April 2009 . 19389260 . 2685135 . 10.1186/1478-811X-7-9 . free .
2. Nygaard G, Di Paolo JA, Hammaker D, Boyle DL, Budas G, Notte GT, Mikaelian I, Barry V, Firestein GS . 6 . Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis . Biochemical Pharmacology . 151 . 282–290 . May 2018 . 29408488 . 10.1016/j.bcp.2018.01.041 . 4863537 .
3. Rampoldi L, Zimbello R, Bortoluzzi S, Tiso N, Valle G, Lanfranchi G, Danieli GA . Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5 . Cytogenetics and Cell Genetics . 78 . 3–4 . 301–3 . 1997 . 9465908 . 10.1159/000134677 . 11577/2469645 . free .
4. Web site: Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5.
5. 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 . 6 . CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1 . Proceedings of the National Academy of Sciences of the United States of America . 106 . 41 . 17389–94 . October 2009 . 19805025 . 2762684 . 10.1073/pnas.0812259106 . 2009PNAS..10617389Y . free .
6. Noguchi T, Takeda K, Matsuzawa A, Saegusa K, Nakano H, Gohda J, Inoue J, Ichijo H . 6 . 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 . The Journal of Biological Chemistry . 280 . 44 . 37033–40 . November 2005 . 16129676 . 10.1074/jbc.M506771200 . free .
7. Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, Ichijo H . Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1 . Molecular and Cellular Biology . 27 . 23 . 8152–63 . December 2007 . 17724081 . 2169188 . 10.1128/MCB.00227-07 .
8. He Y, Zhang W, Zhang R, Zhang H, Min W . SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation . The Journal of Biological Chemistry . 281 . 9 . 5559–66 . March 2006 . 16407264 . 10.1074/jbc.M512338200 . free .
9. Chen J, Fujii K, Zhang L, Roberts T, Fu H . Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism . Proceedings of the National Academy of Sciences of the United States of America . 98 . 14 . 7783–8 . July 2001 . 11427728 . 35419 . 10.1073/pnas.141224398 . 2001PNAS...98.7783C . free .
10. Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H . The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1 . Molecular and Cellular Biology . 21 . 14 . 4818–28 . July 2001 . 11416155 . 87174 . 10.1128/MCB.21.14.4818-4828.2001 .
11. Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D . Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx . Science . 281 . 5384 . 1860–3 . September 1998 . 9743501 . 10.1126/science.281.5384.1860 . 1998Sci...281.1860C . Howard Y. Chang .
12. Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M . Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway . The Journal of Biological Chemistry . 277 . 26 . 23919–26 . June 2002 . 11959862 . 10.1074/jbc.M200838200 . free .
13. Takizawa T, Tatematsu C, Nakanishi Y . Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways . European Journal of Biochemistry . 269 . 24 . 6126–32 . December 2002 . 12473108 . 10.1046/j.1432-1033.2002.03325.x . free .
14. 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 . 6 . Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2 . Nature Cell Biology . 6 . 2 . 146–53 . February 2004 . 14743220 . 10.1038/ncb1093 . 5250125 .
15. 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 . 6 . Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1 . Molecular and Cellular Biology . 22 . 22 . 7721–30 . November 2002 . 12391142 . 134722 . 10.1128/MCB.22.22.7721-7730.2002 .
16. Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, Houghton PJ . Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1) . Molecular Cell . 11 . 6 . 1491–501 . June 2003 . 12820963 . 10.1016/S1097-2765(03)00180-1 . free .
17. Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, Yoshioka K, Ichijo H . 6 . Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade . The Journal of Biological Chemistry . 277 . 43 . 40703–9 . October 2002 . 12189133 . 10.1074/jbc.M202004200 . free . 2297/2692 . free .
18. Hwang IS, Jung YS, Kim E . Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation . FEBS Letters . 529 . 2–3 . 183–7 . October 2002 . 12372597 . 10.1016/S0014-5793(02)03329-X . 9264865 .
19. Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H . Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress . The EMBO Journal . 20 . 21 . 6028–36 . November 2001 . 11689443 . 125685 . 10.1093/emboj/20.21.6028 .
20. Gan B, Peng X, Nagy T, Alcaraz A, Gu H, Guan JL . Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways . The Journal of Cell Biology . 175 . 1 . 121–33 . October 2006 . 17015619 . 2064504 . 10.1083/jcb.200604129 .
21. Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H . 6 . ASK1 is essential for JNK/SAPK activation by TRAF2 . Molecular Cell . 2 . 3 . 389–95 . September 1998 . 9774977 . 10.1016/S1097-2765(00)80283-X . free .
22. Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J, Matsumoto K, Ichijo H . 6 . ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction . The Journal of Biological Chemistry . 275 . 42 . 32747–52 . October 2000 . 10921914 . 10.1074/jbc.M003042200 . free .
23. Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR . Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1) . Oncogene . 18 . 42 . 5814–20 . October 1999 . 10523862 . 10.1038/sj.onc.1202975 . 12132452 .