The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

MAP3K5  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: ASK-1, ASK1, Apoptosis signal-regulating kinase 1, MAPK/ERK kinase kinase 5, MAPKKK5, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of MAP3K5


High impact information on MAP3K5

  • Our findings reveal a strategy by which HIV-1 Nef promotes the killing of bystander cells through the induction of FasL, while simultaneously protecting the HIV-1-infected host cell from these same pro-apoptotic signals through its interference with ASK1 function [6].
  • Here we show that HIV-1 Nef associates with and inhibits apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase that forms a common and key signalling intermediate in the Fas and tumour-necrosis factor-alpha (TNFalpha) death-signalling pathways [6].
  • Fas activation induced Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity [7].
  • Second, interaction with molecules such as Src, Raf, Erk, ASK1 and JNK3 appears to regulate several pathways that result in the activation of MAP kinases [8].
  • These findings suggest that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases [9].

Chemical compound and disease context of MAP3K5


Biological context of MAP3K5


Anatomical context of MAP3K5


Associations of MAP3K5 with chemical compounds

  • In untransfected mammalian cells, ASK1 rapidly associates with TRAF2 in a TNF-dependent manner [21].
  • AIP1 binds to the C-terminal domain of ASK1 via a lysine-rich cluster within the N-terminal C2 domain [22].
  • The relocalized Daxx from the nucleus to the cytoplasm during glucose deprivation participates in a positive regulatory feedback loop by binding to apoptosis signal-regulating kinase (ASK) 1 [23].
  • These results support the hypothesis that the GRX-ASK1 interaction is redox sensitive and regulated in a glutathione-dependent fashion by H(2)O(2) [24].
  • The results presented here indicate that ASK1 forms a complex with the IGF-IR and becomes phosphorylated on tyrosine residue(s) in a manner dependent on IGF-IR activity [25].

Physical interactions of MAP3K5

  • Deletion mutants showed the C-terminal portion of apoptosis signal-regulating kinase 1 (ASK1) bound GRX, and glucose deprivation disrupted binding [24].
  • Cys-250 and Cys-30 in the N-terminal domain of ASK1 are critical for binding of Trx1 and Trx2, respectively [26].
  • It thus appears that the inhibition of NF-kappaB by ASK1 may result at least in part from the disruption of the TRAF6.TAK1 complex formation in the IL-1 signaling pathway [27].
  • Deletion analysis localized the Raf-1 binding site to the N-terminal regulatory fragment of ASK1 [28].
  • In Rh30 cells, ASK1 was found to physically interact with protein phosphatase 5 (PP5), previously identified as a negative regulator of ASK1 [4].

Enzymatic interactions of MAP3K5

  • ASK1 phosphorylates c-Jun N-terminal kinase (JNK) and elicits an apoptotic response [29].
  • In contrast to 14-3-3, AIP1 binds preferentially to dephosphorylated ASK1 [22].
  • Furthermore, TLR2 signalling had a potential to phosphorylate and dephosphorylate ASK1 at Ser83 residue [30].
  • AKT2 interacts with and phosphorylates ASK1 at Ser-83 resulting in inhibition of its kinase activity [31].
  • BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M [32].

Regulatory relationships of MAP3K5


Other interactions of MAP3K5


Analytical, diagnostic and therapeutic context of MAP3K5


  1. Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. Zhou, G., Golden, T., Aragon, I.V., Honkanen, R.E. J. Biol. Chem. (2004) [Pubmed]
  2. ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications. Chibon, F., Mariani, O., Derré, J., Mairal, A., Coindre, J.M., Guillou, L., Sastre, X., Pédeutour, F., Aurias, A. Genes Chromosomes Cancer (2004) [Pubmed]
  3. Direct binding of apoptosis signal-regulating kinase 1 to retinoblastoma protein: novel links between apoptotic signaling and cell cycle machinery. Dasgupta, P., Betts, V., Rastogi, S., Joshi, B., Morris, M., Brennan, B., Ordonez-Ercan, D., Chellappan, S. J. Biol. Chem. (2004) [Pubmed]
  4. Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity. Huang, S., Shu, L., Easton, J., Harwood, F.C., Germain, G.S., Ichijo, H., Houghton, P.J. J. Biol. Chem. (2004) [Pubmed]
  5. Pro-apoptotic tumor necrosis factor-alpha transduction pathway in normal prostate, benign prostatic hyperplasia and prostatic carcinoma. Ricote, M., Royuela, M., García-Tuñón, I., Bethencourt, F.R., Paniagua, R., Fraile, B. J. Urol. (2003) [Pubmed]
  6. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Geleziunas, R., Xu, W., Takeda, K., Ichijo, H., Greene, W.C. Nature (2001) [Pubmed]
  7. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Chang, H.Y., Nishitoh, H., Yang, X., Ichijo, H., Baltimore, D. Science (1998) [Pubmed]
  8. Expanding roles for beta-arrestins as scaffolds and adapters in GPCR signaling and trafficking. Miller, W.E., Lefkowitz, R.J. Curr. Opin. Cell Biol. (2001) [Pubmed]
  9. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Nishitoh, H., Matsuzawa, A., Tobiume, K., Saegusa, K., Takeda, K., Inoue, K., Hori, S., Kakizuka, A., Ichijo, H. Genes Dev. (2002) [Pubmed]
  10. Critical role of ASK1 in the 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Ouyang, M., Shen, X. J. Neurochem. (2006) [Pubmed]
  11. Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines. Mabuchi, S., Ohmichi, M., Kimura, A., Nishio, Y., Arimoto-Ishida, E., Yada-Hashimoto, N., Tasaka, K., Murata, Y. Endocrinology (2004) [Pubmed]
  12. Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway. Wang, Q., Zhang, Q.G., Wu, D.N., Yin, X.H., Zhang, G.Y. Acta Pharmacol. Sin. (2007) [Pubmed]
  13. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. Saitoh, M., Nishitoh, H., Fujii, M., Takeda, K., Tobiume, K., Sawada, Y., Kawabata, M., Miyazono, K., Ichijo, H. EMBO J. (1998) [Pubmed]
  14. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1. Ko, Y.G., Kim, E.Y., Kim, T., Park, H., Park, H.S., Choi, E.J., Kim, S. J. Biol. Chem. (2001) [Pubmed]
  15. Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade. Matsuura, H., Nishitoh, H., Takeda, K., Matsuzawa, A., Amagasa, T., Ito, M., Yoshioka, K., Ichijo, H. J. Biol. Chem. (2002) [Pubmed]
  16. Tumor necrosis factor alpha-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation. Li, X., Zhang, R., Luo, D., Park, S.J., Wang, Q., Kim, Y., Min, W. J. Biol. Chem. (2005) [Pubmed]
  17. Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. Sayama, K., Hanakawa, Y., Shirakata, Y., Yamasaki, K., Sawada, Y., Sun, L., Yamanishi, K., Ichijo, H., Hashimoto, K. J. Biol. Chem. (2001) [Pubmed]
  18. Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates hydrogen peroxide-induced apoptosis in human pulmonary vascular endothelial cells. Machino, T., Hashimoto, S., Maruoka, S., Gon, Y., Hayashi, S., Mizumura, K., Nishitoh, H., Ichijo, H., Horie, T. Crit. Care Med. (2003) [Pubmed]
  19. Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. Wang, X.S., Diener, K., Jannuzzi, D., Trollinger, D., Tan, T.H., Lichenstein, H., Zukowski, M., Yao, Z. J. Biol. Chem. (1996) [Pubmed]
  20. Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways. Takizawa, T., Tatematsu, C., Nakanishi, Y. Eur. J. Biochem. (2002) [Pubmed]
  21. ASK1 is essential for JNK/SAPK activation by TRAF2. Nishitoh, H., Saitoh, M., Mochida, Y., Takeda, K., Nakano, H., Rothe, M., Miyazono, K., Ichijo, H. Mol. Cell (1998) [Pubmed]
  22. AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. Zhang, R., He, X., Liu, W., Lu, M., Hsieh, J.T., Min, W. J. Clin. Invest. (2003) [Pubmed]
  23. Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. Song, J.J., Lee, Y.J. J. Cell Biol. (2005) [Pubmed]
  24. Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2. Song, J.J., Rhee, J.G., Suntharalingam, M., Walsh, S.A., Spitz, D.R., Lee, Y.J. J. Biol. Chem. (2002) [Pubmed]
  25. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). Galvan, V., Logvinova, A., Sperandio, S., Ichijo, H., Bredesen, D.E. J. Biol. Chem. (2003) [Pubmed]
  26. Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Zhang, R., Al-Lamki, R., Bai, L., Streb, J.W., Miano, J.M., Bradley, J., Min, W. Circ. Res. (2004) [Pubmed]
  27. ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction. Mochida, Y., Takeda, K., Saitoh, M., Nishitoh, H., Amagasa, T., Ninomiya-Tsuji, J., Matsumoto, K., Ichijo, H. J. Biol. Chem. (2000) [Pubmed]
  28. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Chen, J., Fujii, K., Zhang, L., Roberts, T., Fu, H. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  29. C-terminus of heat shock protein 70--interacting protein facilitates degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis signal-regulating kinase 1--dependent apoptosis. Hwang, J.R., Zhang, C., Patterson, C. Cell Stress Chaperones (2005) [Pubmed]
  30. Apoptosis signal-regulating kinase 1-mediated sustained p38 mitogen-activated protein kinase activation regulates mycoplasmal lipoprotein- and staphylococcal peptidoglycan-triggered Toll-like receptor 2 signalling pathways. Into, T., Shibata, K. Cell. Microbiol. (2005) [Pubmed]
  31. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. Yuan, Z.Q., Feldman, R.I., Sussman, G.E., Coppola, D., Nicosia, S.V., Cheng, J.Q. J. Biol. Chem. (2003) [Pubmed]
  32. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Yamamoto, K., Ichijo, H., Korsmeyer, S.J. Mol. Cell. Biol. (1999) [Pubmed]
  33. The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1. Zou, X., Tsutsui, T., Ray, D., Blomquist, J.F., Ichijo, H., Ucker, D.S., Kiyokawa, H. Mol. Cell. Biol. (2001) [Pubmed]
  34. Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways. Wang, T.H., Wang, H.S., Ichijo, H., Giannakakou, P., Foster, J.S., Fojo, T., Wimalasena, J. J. Biol. Chem. (1998) [Pubmed]
  35. Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization. Song, J.J., Lee, Y.J. J. Biol. Chem. (2003) [Pubmed]
  36. S-nitrosylation of thioredoxin mediates activation of apoptosis signal-regulating kinase 1. Sumbayev, V.V. Arch. Biochem. Biophys. (2003) [Pubmed]
  37. Protein kinase D specifically mediates apoptosis signal-regulating kinase 1-JNK signaling induced by H2O2 but not tumor necrosis factor. Zhang, W., Zheng, S., Storz, P., Min, W. J. Biol. Chem. (2005) [Pubmed]
  38. Disulfide Bond-mediated multimerization of Ask1 and its reduction by thioredoxin-1 regulate H(2)O(2)-induced c-Jun NH(2)-terminal kinase activation and apoptosis. Nadeau, P.J., Charette, S.J., Toledano, M.B., Landry, J. Mol. Biol. Cell (2007) [Pubmed]
  39. Activation of ASK1 during reperfusion of ischemic spinal cord. Wang, P., Cao, X., Nagel, D.J., Yin, G. Neurosci. Lett. (2007) [Pubmed]
WikiGenes - Universities