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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.[citation needed] 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]


ASK1 has been shown to interact with:


  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. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 14.0 14.1 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.
  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. 16.0 16.1 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. 19.0 19.1 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. 20.0 20.1 20.2 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. 21.0 21.1 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.

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Further reading