map kinase kinase kinase 1


Summary: A 195-kDa zinc finger motif-containing MAP kinase kinase kinase with broad specificity for MAP KINASE KINASES. It localizes to the CYTOSKELETON and can activate a variety of MAP kinase-dependent pathways.

Top Publications

  1. Matsuzawa A, Tseng P, Vallabhapurapu S, Luo J, Zhang W, Wang H, et al. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science. 2008;321:663-8 pubmed publisher
    ..This two-stage signaling mechanism may apply to other innate immune receptors, accounting for spatial and temporal separation of MAPK and IKK signaling. ..
  2. Slattery M, Baumgartner K, Giuliano A, Byers T, Herrick J, Wolff R. Replication of five GWAS-identified loci and breast cancer risk among Hispanic and non-Hispanic white women living in the Southwestern United States. Breast Cancer Res Treat. 2011;129:531-9 pubmed publisher
    ..Our data replicated some of the previously reported GWAS findings. Differences in associations were detected for NHW and Hispanic women by menopausal status and by ER/PR status of tumors. ..
  3. Pearlman A, Loke J, Le Caignec C, White S, Chin L, Friedman A, et al. Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am J Hum Genet. 2010;87:898-904 pubmed publisher
    ..Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination. ..
  4. Zhang L, Deng M, Parthasarathy R, Wang L, Mongan M, Molkentin J, et al. MEKK1 transduces activin signals in keratinocytes to induce actin stress fiber formation and migration. Mol Cell Biol. 2005;25:60-5 pubmed
    ..Together, these pathways lead to the control of actin cytoskeleton reorganization and epithelial cell migration, contributing to the physiologic and pathological effects of activins on epithelial morphogenesis. ..
  5. Whitfield J, Neame S, Paquet L, Bernard O, Ham J. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron. 2001;29:629-43 pubmed
  6. Huser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S, et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 2001;20:1940-51 pubmed
    ..These results strongly argue that MEK kinase activity of Raf-1 is not essential for normal mouse development and that Raf-1 plays a key role in preventing apoptosis. ..
  7. Schlesinger T, Bonvin C, Jarpe M, Fanger G, Cardinaux J, Johnson G, et al. Apoptosis stimulated by the 91-kDa caspase cleavage MEKK1 fragment requires translocation to soluble cellular compartments. J Biol Chem. 2002;277:10283-91 pubmed
  8. He Y, Cai S, Zhang G, Li X, Pan L, Du J. Interfering with cellular signaling pathways enhances sensitization to combined sodium butyrate and GCV treatment in EBV-positive tumor cells. Virus Res. 2008;135:175-80 pubmed publisher
    ..These results suggest that interfering with either the Akt or MEKK1 signaling pathway may be a useful therapeutic strategy to increase the sensitivity of EBV-positive tumor cells to the combination of NaB and GCV. ..
  9. Su S, Suarez Rodriguez M, Krysan P. Genetic interaction and phenotypic analysis of the Arabidopsis MAP kinase pathway mutations mekk1 and mpk4 suggests signaling pathway complexity. FEBS Lett. 2007;581:3171-7 pubmed
    ..Our results suggest that MEKK1 and MPK4 functions are not limited to a single, linear signaling pathway. Instead there appears to be more complexity to the signaling pathways in which these two proteins function. ..

More Information


  1. Gao M, Liu J, Bi D, Zhang Z, Cheng F, Chen S, et al. MEKK1, MKK1/MKK2 and MPK4 function together in a mitogen-activated protein kinase cascade to regulate innate immunity in plants. Cell Res. 2008;18:1190-8 pubmed publisher
    ..In addition, activation of MPK4 by flg22 is impaired in the mkk1 mkk2 double mutants, suggesting that MKK1 and MKK2 function together with MPK4 and MEKK1 in a MAP kinase cascade to negatively regulate innate immune responses in plants. ..
  2. Brun S, Vidal S, Spellman P, Takahashi K, Tricoire H, Lemaitre B. The MAPKKK Mekk1 regulates the expression of Turandot stress genes in response to septic injury in Drosophila. Genes Cells. 2006;11:397-407 pubmed
    ..These results point to a role of Mekk1 in the protection against tissue damage and/or protein degradation and indicate complex interactions between stress and immune pathways in Drosophila. ..
  3. Zhang L, Wang W, Hayashi Y, Jester J, Birk D, Gao M, et al. A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure. EMBO J. 2003;22:4443-54 pubmed
    ..This study also suggests that the signaling mechanisms that control eyelid closure in mammals and dorsal closure in Drosophila are evolutionarily conserved. ..
  4. Xia Y, Wang J, Xu S, Johnson G, Hunter T, Lu Z. MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress. Mol Cell Biol. 2007;27:510-7 pubmed
    ..Furthermore, apoptosis induced by osmotic stress was suppressed by overexpression of c-Jun, indicating that the downregulation of c-Jun promotes apoptosis. ..
  5. Muller J, Ory S, Copeland T, Piwnica Worms H, Morrison D. C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol Cell. 2001;8:983-93 pubmed
  6. Dhillon A, Meikle S, Peyssonnaux C, Grindlay J, Kaiser C, Steen H, et al. A Raf-1 mutant that dissociates MEK/extracellular signal-regulated kinase activation from malignant transformation and differentiation but not proliferation. Mol Cell Biol. 2003;23:1983-93 pubmed
    ..The results further suggest that RafS259 mutants inhibit signaling pathways required to promote these biological processes. ..
  7. Gallagher E, Xu S, Moomaw C, Slaughter C, Cobb M. Binding of JNK/SAPK to MEKK1 is regulated by phosphorylation. J Biol Chem. 2002;277:45785-92 pubmed
    ..Phosphorylation of this site inhibits binding of JNK/SAPK to MEKK1. Thus, we propose a mechanism by which the MEKK1-dependent JNK/SAPK pathway is negatively regulated by PAK through phosphorylation of serine 67. ..
  8. Huijts P, Vreeswijk M, Kroeze Jansema K, Jacobi C, Seynaeve C, Krol Warmerdam E, et al. Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases. Breast Cancer Res. 2007;9:R78 pubmed
    ..These findings provide interesting new clues for further research on these low-risk susceptibility alleles. ..
  9. Lu Z, Xu S, Joazeiro C, Cobb M, Hunter T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol Cell. 2002;9:945-56 pubmed
    ..Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity. ..
  10. Chadee D, Yuasa T, Kyriakis J. Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol. 2002;22:737-49 pubmed
    ..These results represent the first activation of MEKK1 in vitro using purified proteins and suggest a mechanism for MEKK1 activation involving induced oligomerization and consequent autophosphorylation mediated by upstream proteins. ..
  11. Ortega Perez I, Cano E, Were F, Villar M, Vazquez J, Redondo J. c-Jun N-terminal kinase (JNK) positively regulates NFATc2 transactivation through phosphorylation within the N-terminal regulatory domain. J Biol Chem. 2005;280:20867-78 pubmed
    ..Our results indicate that, unlike other NFAT members, the transcriptional activity of NFATc2 is up-regulated by JNK. JNK-mediated phosphorylation of NFATs thus appears to play a differential physiological role among NFAT family members. ..
  12. Hallsworth M, Moir L, Lai D, Hirst S. Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. Am J Respir Crit Care Med. 2001;164:688-97 pubmed
  13. Kim J, Joe C, Choi E. Role of receptor-interacting protein in tumor necrosis factor-alpha -dependent MEKK1 activation. J Biol Chem. 2001;276:27064-70 pubmed
    ..Taken together, our results suggest that RIP phosphorylates and activates MEKK1 and that RIP is involved in TNF-alpha-induced MEKK1 activation. ..
  14. Seong K, Li D, Shimizu H, Nakamura R, Ishii S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell. 2011;145:1049-61 pubmed publisher
    ..The results suggest a mechanism by which the effects of stress are inherited epigenetically via the regulation of a tight chromatin structure. ..
  15. Gallagher E, Gutowski S, Sternweis P, Cobb M. RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. J Biol Chem. 2004;279:1872-7 pubmed
    ..In summary, we have characterized a novel point at which Rho GTPases impinge upon the regulation and function of MEKK1. ..
  16. Miao Y, Laun T, Smykowski A, Zentgraf U. Arabidopsis MEKK1 can take a short cut: it can directly interact with senescence-related WRKY53 transcription factor on the protein level and can bind to its promoter. Plant Mol Biol. 2007;65:63-76 pubmed
    ..Thus, MEKK1 might be able to take a very direct short cut in mitogen-activated protein kinase (MAPK) signalling by directly phosphorylating a transcription factor. ..
  17. Cross J, Templeton D. Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain. Biochem J. 2004;381:675-83 pubmed
    ..Our results support a model whereby the redox environment within the cell selectively regulates stress signalling through MEKK1 versus ASK1, and may thereby participate in the induction of apoptosis by oxidative stress. ..
  18. Suarez Rodriguez M, Adams Phillips L, Liu Y, Wang H, Su S, Jester P, et al. MEKK1 is required for flg22-induced MPK4 activation in Arabidopsis plants. Plant Physiol. 2007;143:661-9 pubmed
    ..Our results indicate that MEKK1 acts upstream of MPK4 as a negative regulator of pathogen response pathways, a function that may not require MEKK1's full kinase activity. ..
  19. Easton D, Pooley K, Dunning A, Pharoah P, Thompson D, Ballinger D, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447:1087-93 pubmed
    ..05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. ..
  20. Gallagher E, Enzler T, Matsuzawa A, Anzelon Mills A, Otero D, Holzer R, et al. Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunol. 2007;8:57-63 pubmed
    ..Our data emphasize that MEKK1 is an essential component of signaling cascades needed for thymus-dependent antigen-induced B cell proliferation and antibody production. ..
  21. Miller S, Malotky E, O Bryan J. Analysis of the role of ubiquitin-interacting motifs in ubiquitin binding and ubiquitylation. J Biol Chem. 2004;279:33528-37 pubmed
    ..Our results suggest a new model for the ubiquitylation of UIM-containing proteins. ..
  22. Garcia Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J, Richesson D, et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet. 2008;4:e1000054 pubmed publisher
    ..Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment. ..
  23. Kwan R, Burnside J, Kurosaki T, Cheng G. MEKK1 is essential for DT40 cell apoptosis in response to microtubule disruption. Mol Cell Biol. 2001;21:7183-90 pubmed
  24. Rebbeck T, DeMichele A, Tran T, Panossian S, Bunin G, Troxel A, et al. Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women. Carcinogenesis. 2009;30:269-74 pubmed publisher
    ..We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women...
  25. Champion A, Picaud A, Henry Y. Reassessing the MAP3K and MAP4K relationships. Trends Plant Sci. 2004;9:123-9 pubmed
  26. Witowsky J, Johnson G. Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. J Biol Chem. 2003;278:1403-6 pubmed
    ..MEKK1 ubiquitylation represents a mechanism for inhibiting the ability of a protein kinase to phosphorylate substrates and regulate downstream signaling pathways. ..
  27. Bonnesen B, Orskov C, Rasmussen S, Holst P, Christensen J, Eriksen K, et al. MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver. Blood. 2005;106:3396-404 pubmed
  28. Enzler T, Chang X, Facchinetti V, Melino G, Karin M, Su B, et al. MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression. J Immunol. 2009;183:3831-8 pubmed publisher
    ..MEKK1 phosphorylation on Thr(1381) is observed during Th2 differentiation, but not under Th1 differentiation. Both Itch and the MEKK1 kinase domain are important for Il4 and Il6 cytokine gene expression under Th2 conditions. ..
  29. Kong Q, Qu N, Gao M, Zhang Z, Ding X, Yang F, et al. The MEKK1-MKK1/MKK2-MPK4 kinase cascade negatively regulates immunity mediated by a mitogen-activated protein kinase kinase kinase in Arabidopsis. Plant Cell. 2012;24:2225-36 pubmed publisher
    ..Taken together, our data suggest that the MEKK1-MKK1/MKK2-MPK4 kinase cascade negatively regulates MEKK2 and activation of MEKK2 triggers SUMM2-mediated immune responses. ..
  30. Ichimura K, Casais C, Peck S, Shinozaki K, Shirasu K. MEKK1 is required for MPK4 activation and regulates tissue-specific and temperature-dependent cell death in Arabidopsis. J Biol Chem. 2006;281:36969-76 pubmed
  31. Ellis M, Ding L, Shen D, Luo J, Suman V, Wallis J, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486:353-60 pubmed publisher
    ..Prospective clinical trials based on these findings will require comprehensive genome sequencing. ..
  32. Guan Z, Buckman S, Pentland A, Templeton D, Morrison A. Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. J Biol Chem. 1998;273:12901-8 pubmed
    ..Together, this data suggests a potential role for the MEKK1 --> SEK1/MKK4 --> p38 MAPK -->--> Cox-2 cascade linking members of the MAPK pathway with prostaglandin biosynthesis. ..
  33. Widmann C, Gerwins P, Johnson N, Jarpe M, Johnson G. MEK kinase 1, a substrate for DEVD-directed caspases, is involved in genotoxin-induced apoptosis. Mol Cell Biol. 1998;18:2416-29 pubmed
    ..MEKK1 and caspases are predicted to be part of an amplification loop to increase caspase activity during apoptosis. ..
  34. Huttunen H, Kuja Panula J, Sorci G, Agneletti A, Donato R, Rauvala H. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem. 2000;275:40096-105 pubmed
    ..We suggest that RAGE is a signal-transducing receptor for both trophic and toxic effects of S100B. ..
  35. Yujiri T, Sather S, Fanger G, Johnson G. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science. 1998;282:1911-4 pubmed
    ..When activated by specific stresses that alter cell shape and the cytoskeleton, MEKK1 signals to protect cells from apoptosis. ..
  36. Hu W, Johnson H, Shu H. Tumor necrosis factor-related apoptosis-inducing ligand receptors signal NF-kappaB and JNK activation and apoptosis through distinct pathways. J Biol Chem. 1999;274:30603-10 pubmed
    ..These findings suggest that TRAIL receptors induce apoptosis, NF-kappaB and JNK activation through distinct signaling pathways, and activation of NF-kappaB is not sufficient for protecting cells from TRAIL-induced apoptosis. ..
  37. Xia Y, Makris C, Su B, Li E, Yang J, Nemerow G, et al. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. Proc Natl Acad Sci U S A. 2000;97:5243-8 pubmed
    ..MEKK1 is also essential for induction of embryonic stem cell migration by serum factors, but is not required for activation of other MAPKs or the IkappaB kinase signaling cascade. ..
  38. Yujiri T, Ware M, Widmann C, Oyer R, Russell D, Chan E, et al. MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Proc Natl Acad Sci U S A. 2000;97:7272-7 pubmed
    ..Thus, MEKK1 senses microtubule integrity, contributes to the regulation of fibroblast and epithelial cell migration, and is required for activation of JNK but not NF-kappaB in response to selected stress stimuli. ..
  39. See R, Calvo D, Kawa H, Luke M, Yuan Z, Shi Y. Stimulation of p300-mediated transcription by the kinase MEKK1. J Biol Chem. 2001;276:16310-7 pubmed
    ..Taken together, these results identify MEKK1 as a kinase that is likely to be involved in the regulation of the transactivation potential of p300 and support a role of p300 in MEKK1-induced apoptosis. ..
  40. Lee F, Peters R, Dang L, Maniatis T. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proc Natl Acad Sci U S A. 1998;95:9319-24 pubmed
    ..We conclude that IKK-alpha and IKK-beta can mediate the NF-kappaB-inducing activity of MEKK1. ..
  41. Mendoza F, Ishdorj G, Hu X, Gibson S. Death receptor-4 (DR4) expression is regulated by transcription factor NF-kappaB in response to etoposide treatment. Apoptosis. 2008;13:756-70 pubmed publisher
    ..Expression of the kinase inactive MEKK1 (MEKK1-KM) abrogates the up-regulation of DR4 after etoposide treatment. Taken together, NF-kappaB plays a role in up-regulation of DR4 following etoposide treatment. ..
  42. Huang Y, Fang Y, Dziadyk J, Norris J, Fan W. The possible correlation between activation of NF-kappaB/IkappaB pathway and the susceptibility of tumor cells to paclitaxel-induced apoptosis. Oncol Res. 2002;13:113-22 pubmed
    ..These findings suggest that the activation of NF-kappaB/IkappaBalpha signaling pathway might play an important role in determining the susceptibility of tumor cells to paclitaxel-induced apoptosis. ..
  43. Chou F, Tseng T, Chen J, Wang H, Wang C. Induced proliferation of human MRC-5 cells by nitrogen oxides via direct and indirect activation of MEKK1, JNK, and p38 signals. Toxicol Appl Pharmacol. 2002;181:203-8 pubmed
    ..Therefore, the NOx-induced cell proliferation via activation of MEKK1, JNK1, and p38 might contribute to lung tissue damage caused by NOx pollutants. ..
  44. Balasubramanian S, Zhu L, Eckert R. Apigenin inhibition of involucrin gene expression is associated with a specific reduction in phosphorylation of protein kinase Cdelta Tyr311. J Biol Chem. 2006;281:36162-72 pubmed
    ..Additional studies show that the apigenin-dependent suppression of differentiation is associated with reduced cell proliferation but that there is no evidence of apoptosis. ..
  45. Clark N, Marinis J, Cobb B, Abbott D. MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Curr Biol. 2008;18:1402-8 pubmed publisher
    ..These biochemical findings suggest that basal inhibition of the NOD2-driven NFkappaB pathway by MEKK4 could be important in the pathogenesis of Crohn's disease. ..
  46. Shimoke K, Amano H, Kishi S, Uchida H, Kudo M, Ikeuchi T. Nerve growth factor attenuates endoplasmic reticulum stress-mediated apoptosis via suppression of caspase-12 activity. J Biochem. 2004;135:439-46 pubmed
    ..These results demonstrate that the inactivation of caspase-12 via the NGF-mediated PI3-K signaling pathway leads to inactivation of the caspase cascade including caspase-3 and -9. ..
  47. Zhong J, Kyriakis J. Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization. Mol Cell Biol. 2004;24:9165-75 pubmed
    ..Our results identify a physiologic function and unexpected mode of regulation for GCK. ..
  48. Lee Y, Malbon C, Wang H. G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation. J Biol Chem. 2004;279:54896-904 pubmed
    ..In a concerted effort, RhoA in tandem with Cdc42 and Rac1 activates the MEKK1/4, MEK1/MKK4, and JNK cascade, thereby stimulating formation of primitive endoderm. ..
  49. Wang W, Chen J, Liao R, Deng Q, Zhou J, Huang S, et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002;22:3389-403 pubmed
    ..These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells. ..
  50. Siu Y, Ching Y, Jin D. Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation. Mol Biol Cell. 2008;19:4750-61 pubmed publisher
    ..Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling. ..
  51. Susaki K, Chiba C. MEK mediates in vitro neural transdifferentiation of the adult newt retinal pigment epithelium cells: Is FGF2 an induction factor?. Pigment Cell Res. 2007;20:364-79 pubmed
  52. Jakobs A, Himstedt F, Funk M, Korn B, Gaestel M, Niedenthal R. Ubc9 fusion-directed SUMOylation identifies constitutive and inducible SUMOylation. Nucleic Acids Res. 2007;35:e109 pubmed
    ..Hence, UFDS is appropriate for the identification and characterization of constitutive and, more importantly, induced protein SUMOylation in vivo. ..
  53. Deng M, Chen W, Takatori A, Peng Z, Zhang L, Mongan M, et al. A role for the mitogen-activated protein kinase kinase kinase 1 in epithelial wound healing. Mol Biol Cell. 2006;17:3446-55 pubmed
    ..Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization. ..