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.
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 deubiqutination. Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as post-transcriptional.
^ abcNygaard G, Di Paolo JA, Hammaker D, Boyle DL, Budas G, Notte GT, et al. (May 2018). "Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis". Biochemical Pharmacology. 151: 282–290. doi:10.1016/j.bcp.2018.01.041. PMID29408488.
^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". Cytogenetics and Cell Genetics. 78 (3–4): 301–3. doi:10.1159/000134677. PMID9465908.
^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". The Journal of Biological Chemistry. 277 (26): 23919–26. doi:10.1074/jbc.M200838200. PMID11959862.
^Takizawa T, Tatematsu C, Nakanishi Y (December 2002). "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. doi:10.1046/j.1432-1033.2002.03325.x. PMID12473108.
^Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, et al. (February 2004). "Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2". Nature Cell Biology. 6 (2): 146–53. doi:10.1038/ncb1093. PMID14743220.
^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)". Molecular Cell. 11 (6): 1491–501. doi:10.1016/S1097-2765(03)00180-1. PMID12820963.
^ abMochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J, et al. (October 2000). "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction". The Journal of Biological Chemistry. 275 (42): 32747–52. doi:10.1074/jbc.M003042200. PMID10921914.
^Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, et al. (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". The Journal of Biological Chemistry. 277 (43): 40703–9. doi:10.1074/jbc.M202004200. PMID12189133.
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. PMID16517200.
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. PMID17244475.
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. PMID8940179.
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. PMID8974401.
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. PMID9743501.
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. PMID9774977.
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. PMID9875215.
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. PMID11096076.
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. PMID11278289.
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. doi:10.1038/35071111. PMID11298454.