Gene Symbol: MAPKKK6
Description: mitogen-activated protein kinase kinase kinase 6
Alias: ASK2, MAPKKK6, MEKK6, mitogen-activated protein kinase kinase kinase 6, apoptosis signal-regulating kinase 2
Species: human
Products:     MAPKKK6

Top Publications

  1. Takeda K, Shimozono R, Noguchi T, Umeda T, Morimoto Y, Naguro I, et al. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1. J Biol Chem. 2007;282:7522-31 pubmed
    ..Here we show that ASK2, a highly related serine/threonine kinase to ASK1, also functions as a MAP3K only in a heteromeric complex with ..
  2. Ortner E, Moelling K. Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling. Biochem Biophys Res Commun. 2007;362:454-9 pubmed
    Apoptosis signal-regulating kinase 2 (ASK2) is an interaction partner of the highly related ASK1. Here, we describe a regulatory function of ASK2 in stress signaling-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP)...
  3. Iriyama T, Takeda K, Nakamura H, Morimoto Y, Kuroiwa T, Mizukami J, et al. ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis. EMBO J. 2009;28:843-53 pubmed publisher
    ..Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially ..
  4. Eto N, Miyagishi M, Inagi R, Fujita T, Nangaku M. Mitogen-activated protein 3 kinase 6 mediates angiogenic and tumorigenic effects via vascular endothelial growth factor expression. Am J Pathol. 2009;174:1553-63 pubmed publisher
    ..Screening using an siRNA library revealed that MAPKKK6 (MEKK6/MAP3K6) regulates VEGF expression under both normoxic and hypoxic conditions in vitro, although the ..
  5. Newton V, Ali S, Duddy G, Whitmarsh A, Gardiner N. Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice. PLoS ONE. 2014;9:e107437 pubmed publisher
    ..However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field...
  6. Guo S, Liang Y, Murphy S, Huang A, Shen H, Kelly D, et al. A rapid and high content assay that measures cyto-ID-stained autophagic compartments and estimates autophagy flux with potential clinical applications. Autophagy. 2015;11:560-72 pubmed publisher
  7. Song Y, Estrada D, Johnson R, Kim S, Lee S, MacCoss M, et al. Distinct roles of FKF1, Gigantea, and Zeitlupe proteins in the regulation of Constans stability in Arabidopsis photoperiodic flowering. Proc Natl Acad Sci U S A. 2014;111:17672-7 pubmed publisher
    ..protein 1 (Skp1)/Cullin(CUL)/F-box complex through interactions with Arabidopsis Skp1-like 1 (ASK1), ASK2, and CUL1 proteins and mainly interacts with GI protein in vivo...
  8. Petrovchich I, Ford J. Genetic predisposition to gastric cancer. Semin Oncol. 2016;43:554-559 pubmed publisher
  9. Zhang Y, Wang C, Lin Q, Gao F, Ma Y, Zhang M, et al. Genome-wide analysis of phylogeny, expression profile and sub-cellular localization of SKP1-Like genes in wild tomato. Plant Sci. 2015;238:105-14 pubmed publisher
    ..Based on phylogenetic analysis, expression profiles and protein interaction property, we proposed that tomato SSK1 and SSK2 might have similar function to ASK1 and ASK2 in Arabidopsis.

More Information


  1. Sugimoto S, Komatsu H, Morohoshi Y, Kanai T. Recognition of and recent issues in hereditary diffuse gastric cancer. J Gastroenterol. 2015;50:831-43 pubmed publisher
    ..CDH1 testing, including analyses of large genomic rearrangements, should be recommended even in countries where few HDGC cases have been reported. ..
  2. Imamura K, Yoshitane H, Hattori K, Yamaguchi M, Yoshida K, Okubo T, et al. ASK family kinases mediate cellular stress and redox signaling to circadian clock. Proc Natl Acad Sci U S A. 2018;115:3646-3651 pubmed publisher
    ..In behavioral analysis, Ask1, Ask2, and Ask3 triple-KO mice exhibited compromised light responses of the circadian period and phase in ..
  3. Place D, Samir P, Karki R, Briard B, Vogel P, Kanneganti T. ASK Family Kinases Are Required for Optimal NLRP3 Inflammasome Priming. Am J Pathol. 2018;188:1021-1030 pubmed publisher
    ..Single knockouts of either ASK1 or ASK2 showed a partial role for both ASK1 and ASK2 in NLRP3 up-regulation in response to lipopolysaccharide or B...
  4. Almasi R, Miller W, Ziegler Graff V. Mild and severe cereal yellow dwarf viruses differ in silencing suppressor efficiency of the P0 protein. Virus Res. 2015;208:199-206 pubmed publisher
    ..Finally both P0(CY-RPV) and P0(CY-RPS) interacted in yeast cells with ASK2, a component of an E3-ubiquitin ligase, with distinct affinities.
  5. Wang X, Diener K, Tan T, Yao Z. MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. Biochem Biophys Res Commun. 1998;253:33-7 pubmed contain all 11 kinase subdomains and shares 45% amino acid identity with MAPKKK5 and thus is designated MAPKKK6. The interaction of MAPKKK6 with MAPKKK5 in vivo was confirmed by coexpression of MAPKKK5 and MAPKKK6 in 293 ..
  6. Ryuno H, Naguro I, Kamiyama M. ASK family and cancer. Adv Biol Regul. 2017;66:72-84 pubmed publisher
    ..that respond to various types of stressors are apoptosis signal-regulating kinase (ASK) family members; ASK1, ASK2 and ASK3...
  7. Liu T, Zhou H, Min W. ASK family in cardiovascular biology and medicine. Adv Biol Regul. 2017;66:54-62 pubmed publisher
    ..Apoptosis signal-regulating kinase (ASK) family members ASK1, ASK2 and ASK3 are the key molecules in MAPK signal cascades and are activated by various stresses...
  8. Okazaki T, Higuchi M, Takeda K, Iwatsuki Horimoto K, Kiso M, Miyagishi M, et al. The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response. Sci Signal. 2015;8:ra78 pubmed publisher
    ..In contrast, we found that the MAPKKK ASK2, a modulator of ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing IFNB expression...
  9. Gaston D, Hansford S, Oliveira C, Nightingale M, Pinheiro H, Macgillivray C, et al. Germline mutations in MAP3K6 are associated with familial gastric cancer. PLoS Genet. 2014;10:e1004669 pubmed publisher
  10. Federspiel J, Codreanu S, Palubinsky A, Winland A, Betanzos C, McLaughlin B, et al. Assembly Dynamics and Stoichiometry of the Apoptosis Signal-regulating Kinase (ASK) Signalosome in Response to Electrophile Stress. Mol Cell Proteomics. 2016;15:1947-61 pubmed publisher
    ..stable isotope dilution assays to quantify protein stoichiometry in the ASK signalosome complex and identified ASK2 at a 1:1 stoichiometric ratio with ASK1 and 14-3-3 proteins (YWHAQ, YWHAB, YWHAH, and YWHAE) collectively at a 0...
  11. Cockrell L, Puckett M, Goldman E, Khuri F, Fu H. Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome. Oncogene. 2010;29:822-30 pubmed publisher
    ..a novel mechanism controlling signal relay between two MAP3Ks, apoptosis signal-regulating kinase (ASK) 1 and ASK2. We show that ASK2 specifically interacts with 14-3-3 proteins through phosphorylated S964...
  12. Nishida T, Hattori K, Watanabe K. The regulatory and signaling mechanisms of the ASK family. Adv Biol Regul. 2017;66:2-22 pubmed publisher
    ..1 (ASK1) was identified as a MAP3K that activates the JNK and p38 pathways, and subsequent studies have reported ASK2 and ASK3 as members of the ASK family...
  13. Liu X, Zhang P, Ji K, Zhang J, Yang S, Du B, et al. Cyclin-dependent kinase 5 regulates MAPK/ERK signaling in the skin of mice. Acta Histochem. 2018;120:15-21 pubmed publisher
    ..Given that MAP3K6 was inhibited in two directions, this mechanism can provide insight into the contributions of the MAPK/ERK pathway to the inhibition of melanin production. ..
  14. Arning L, Monte D, Hansen W, Wieczorek S, Jagiello P, Akkad D, et al. ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. J Mol Med (Berl). 2008;86:485-90 pubmed publisher
  15. Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, et al. Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. EMBO J. 2001;20:6028-36 pubmed
    ..PP5 inhibited not only H(2)O(2)-induced sustained activation of ASK1 but also ASK1-dependent apoptosis. Thus, PP5 appears to act as a physiological inhibitor of ASK1-JNK/p38 pathways by negative feedback. ..