map kinase kinase kinase 4


Summary: A 180-kDa MAP kinase kinase kinase with specificity for MAP KINASE KINASE 4 and MAP KINASE KINASE 6.

Top Publications

  1. Takekawa M, Saito H. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell. 1998;95:521-30 pubmed
    ..We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses. ..
  2. Yamauchi J, Miyamoto Y, Murabe M, Fujiwara Y, Sanbe A, Fujita Y, et al. Gadd45a, the gene induced by the mood stabilizer valproic acid, regulates neurite outgrowth through JNK and the substrate paxillin in N1E-115 neuroblastoma cells. Exp Cell Res. 2007;313:1886-96 pubmed
    ..Taken together, these results suggest that upregulation of Gadd45a explains one of the mechanisms whereby VPA induces the neurotrophic effect, providing a new role of Gadd45a in neurite outgrowth. ..
  3. Sarkisian M, Bartley C, Chi H, Nakamura F, Hashimoto Torii K, Torii M, et al. MEKK4 signaling regulates filamin expression and neuronal migration. Neuron. 2006;52:789-801 pubmed
    ..Collectively, our results demonstrate a link between MEKK4 and Fln-A that impacts neuronal migration initiation and provides insight into the pathogenesis of human PVH. ..
  4. Abell A, Rivera Perez J, Cuevas B, Uhlik M, Sather S, Johnson N, et al. Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. Mol Cell Biol. 2005;25:8948-59 pubmed
    ..Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation. ..
  5. Abell A, Johnson G. MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J Biol Chem. 2005;280:35793-6 pubmed
    ..The findings identify MEKK4 as the MAPK kinase kinase for TRAF4 regulation of the JNK pathway. ..
  6. Abell A, Jordan N, Huang W, Prat A, Midland A, Johnson N, et al. MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells. Cell Stem Cell. 2011;8:525-37 pubmed publisher
    ..Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer. ..
  7. Takekawa M, Posas F, Saito H. A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J. 1997;16:4973-82 pubmed
    ..These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway, and is also a minor mediator of the JNK pathway. ..
  8. Bettinger B, Amberg D. The MEK kinases MEKK4/Ssk2p facilitate complexity in the stress signaling responses of diverse systems. J Cell Biochem. 2007;101:34-43 pubmed
    ..We will also highlight evidence supporting a role for MEKK4 in mediating actin recovery following osmotic shock in mammalian cells. ..
  9. Aissouni Y, Zapart G, Iovanna J, Dikic I, Soubeyran P. CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway. Biochem Biophys Res Commun. 2005;338:808-14 pubmed
    ..Taken together, these results indicate a novel role for CIN85 in the regulation of cellular stress response via the MAPK pathways. ..

More Information


  1. Chi H, Lu B, Takekawa M, Davis R, Flavell R. GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. EMBO J. 2004;23:1576-86 pubmed
    ..During Th1 differentiation, the GADD45beta/GADD45gamma/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNgamma production in a process independent of STAT4. ..
  2. Chi H, Sarkisian M, Rakic P, Flavell R. Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proc Natl Acad Sci U S A. 2005;102:3846-51 pubmed
    ..Here, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepithelium...
  3. Bogani D, Siggers P, Brixey R, Warr N, Beddow S, Edwards J, et al. Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biol. 2009;7:e1000196 pubmed publisher
  4. Miyake Z, Takekawa M, Ge Q, Saito H. Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Mol Cell Biol. 2007;27:2765-76 pubmed
    ..Constitutively active MTK1 mutants induced the same events, but in the absence of GADD45. ..
  5. Sollome J, Thavathiru E, Camenisch T, Vaillancourt R. HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4). Cell Signal. 2014;26:70-82 pubmed publisher
    ..Cell migration is required for cancer cell metastasis, which is the major cause of cancer patient mortality. We identify MTK1 in the HER2/HER3-HRG mediated extracellular acidification and cell migration pathway in breast cancer cells. ..
  6. Warr N, Carré G, Siggers P, Faleato J, Brixey R, Pope M, et al. Gadd45? and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Dev Cell. 2012;23:1020-31 pubmed publisher
    ..Taken together, our data suggest a requirement for GADD45? in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse. ..
  7. 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. ..
  8. Derbyshire Z, Halfter U, Heimark R, Sy T, Vaillancourt R. Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II. Mol Cell Biochem. 2005;271:77-90 pubmed
  9. Weizman N, Shiloh Y, Barzilai A. Contribution of the Atm protein to maintaining cellular homeostasis evidenced by continuous activation of the AP-1 pathway in Atm-deficient brains. J Biol Chem. 2003;278:6741-7 pubmed
    ..Our results further demonstrate that inactivation of the ATM gene results in a state of constant stress. ..
  10. Huang J, Tu Z, Lee F. Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity. Biochem Biophys Res Commun. 2003;303:532-40 pubmed
    ..Interestingly, the spectrum of mutations in subdomain X of MEKK2 that affects its activity is overlapping with but not identical to those that have effects on MEKK1. Thus, mutations in subdomain X differentially affect MEKK2 and MEKK1. ..
  11. Homer C, Kabi A, Marina Garcia N, Sreekumar A, Nesvizhskii A, Nickerson K, et al. A dual role for receptor-interacting protein kinase 2 (RIP2) kinase activity in nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J Biol Chem. 2012;287:25565-76 pubmed publisher
    ..RIP2 both sends a positive autophagy signal through activation of p38 MAPK and relieves repression of autophagy mediated by the phosphatase PP2A. ..
  12. Mizote I, Yamaguchi O, Hikoso S, Takeda T, Taneike M, Oka T, et al. Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure. J Mol Cell Cardiol. 2010;48:302-9 pubmed publisher
    ..Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure. ..
  13. Gordon P, Soliman M, Bose P, Trinh Q, Sensen C, Riabowol K. Interspecies data mining to predict novel ING-protein interactions in human. BMC Genomics. 2008;9:426 pubmed publisher
    ..We therefore propose that the weak (low signal to noise ratio) data from large-scale interaction datasets are currently underutilized. ..
  14. Andreone T, O Connor M, Denenberg A, Hake P, Zingarelli B. Poly(ADP-ribose) polymerase-1 regulates activation of activator protein-1 in murine fibroblasts. J Immunol. 2003;170:2113-20 pubmed
    ..No DNA binding of heat shock factor-1 was observed in PARP-1-deficient cells. These data demonstrate that PARP-1 plays a pivotal role in the modulation of transcription. ..
  15. Luo W, Ng W, Jin L, Ye Z, Han J, Lin S. Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. J Biol Chem. 2003;278:37451-8 pubmed
    ..Our findings will provide new insights into how scaffold proteins mediate ultimate activation of different mitogen-activated protein kinase kinase kinases. ..
  16. Mita H, Tsutsui J, Takekawa M, Witten E, Saito H. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol Cell Biol. 2002;22:4544-55 pubmed
    ..These MTK1 mutants are constitutively active, in both yeast and mammalian cells. A model of MTK1 autoinhibition by the N-terminal inhibitory domain and activation by GADD45 binding is presented. ..
  17. Stevens M, Parker P, Vaillancourt R, Camenisch T. MEKK4 regulates developmental EMT in the embryonic heart. Dev Dyn. 2006;235:2761-70 pubmed
    ..Thus, the kinase activity of MEKK4 is essential, but not sufficient, to support developmental EMT. This knowledge provides a basis to understand how MEKK4 may integrate signaling cascades controlling heart development. ..
  18. van der Pouw Kraan C, Baggen J, van Bodegraven A, Mulder C, Zwiers A, Geerts D, et al. Defective IL-1A expression in patients with Crohn's disease is related to attenuated MAP3K4 signaling. Hum Immunol. 2012;73:912-9 pubmed publisher
    ..This confirms the hypothesis that CD patients, despite their massive intestinal inflammation, suffer from a relative immune deficiency in TLR-mediated cytokine production. ..
  19. Sapkota G. The TGF?-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1. Open Biol. 2013;3:130067 pubmed publisher
  20. Yang J, Zhu H, Murphy T, Ouyang W, Murphy K. IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nat Immunol. 2001;2:157-64 pubmed
    ..Thus, the synergy between IL-12 and IL-18 may involve GADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production. ..
  21. 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. ..
  22. Bonvin C, Guillon A, van Bemmelen M, Gerwins P, Johnson G, Widmann C. Role of the amino-terminal domains of MEKKs in the activation of NF kappa B and MAPK pathways and in the regulation of cell proliferation and apoptosis. Cell Signal. 2002;14:123-31 pubmed
    ..Our data show that the N-terminal domain of the MEKKs determines the specificity and the strength of activation of various intracellular signaling pathways and cellular responses. ..
  23. Le Gallo M, O Hara A, Rudd M, Urick M, Hansen N, O Neil N, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet. 2012;44:1310-5 pubmed publisher
  24. Tsuchimochi K, Otero M, Dragomir C, Plumb D, Zerbini L, Libermann T, et al. GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. J Biol Chem. 2010;285:8395-407 pubmed publisher
    ..Collectively, we have uncovered a novel molecular mechanism linking GADD45beta via the MTK1/MKK3/6/p38 axis to C/EBPbeta-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes. ..
  25. Kedar V, Darby M, Williams J, Blackshear P. Phosphorylation of human tristetraprolin in response to its interaction with the Cbl interacting protein CIN85. PLoS ONE. 2010;5:e9588 pubmed publisher
    ..The functional consequences to each of the members of this putative complex remain to be determined. ..
  26. Grucza R, Johnson E, Krueger R, Breslau N, Saccone N, Chen L, et al. Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. Addict Biol. 2010;15:346-57 pubmed publisher
    ..Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery. ..
  27. Abell A, Granger D, Johnson G. MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta. J Biol Chem. 2007;282:30476-84 pubmed
    ..Thus, control of MEKK4 dimerization is regulated both positively and negatively by its interaction with specific proteins. ..
  28. Sun B, Kim J, Nguyen H, Oh S, Kim S, Choi S, et al. MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation. Oncol Rep. 2011;25:537-44 pubmed publisher
    ..Taken together, we show herein that the upstream molecule of the TRAIL-induced MAPK activation is MEKK, as opposed to ASK1, via the mediation of its signal through JNK/p38 in a caspase-8-dependent manner. ..
  29. Keil E, Höcker R, Schuster M, Essmann F, Ueffing N, Hoffman B, et al. Phosphorylation of Atg5 by the Gadd45?-MEKK4-p38 pathway inhibits autophagy. Cell Death Differ. 2013;20:321-32 pubmed publisher
    ..Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45?/MEKK4 negatively regulates the autophagic process. ..
  30. Champion A, Picaud A, Henry Y. Reassessing the MAP3K and MAP4K relationships. Trends Plant Sci. 2004;9:123-9 pubmed
  31. Ray R, Jin S, Bavaria M, Johnson L. Regulation of JNK activity in the apoptotic response of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;300:G761-70 pubmed publisher
    ..Taken together, these results suggest that MKP1 activity determines the duration of JNK1/2 and p38 activation and, thereby, apoptosis in response to TNF + CPT. ..
  32. Wang H, Kanungo J, Malbon C. Expression of Galpha 13 (Q226L) induces P19 stem cells to primitive endoderm via MEKK1, 2, or 4. J Biol Chem. 2002;277:3530-6 pubmed
  33. Kim J, Kang D, Sun B, Kim J, Song J. TRAIL/MEKK4/p38/HSP27/Akt survival network is biphasically modulated by the Src/CIN85/c-Cbl complex. Cell Signal. 2013;25:372-9 pubmed publisher
    ..Taken together, these data demonstrate that phosphorylated p38/HSP27 as biphasic modulators act in conjunction with CIN85 to determine whether cells survive or die in response to apoptotic stress. ..
  34. Owen G, Achilonu I, Dirr H. High yield purification of JNK1?1 and activation by in vitro reconstitution of the MEKK1?MKK4?JNK MAPK phosphorylation cascade. Protein Expr Purif. 2013;87:87-99 pubmed publisher
    ..Activated JNK1?1 was thereafter able to phosphorylate ATF2 with high catalytic efficiency. ..
  35. Hagemann C, Blank J. The ups and downs of MEK kinase interactions. Cell Signal. 2001;13:863-75 pubmed
    ..This review summarises our current knowledge concerning the regulation and function of MEKK family members, with particular emphasis on those factors capable of directly interacting with distinct MEKK isoforms. ..
  36. Abell A, Granger D, Johnson N, Vincent Jordan N, Dibble C, Johnson G. Trophoblast stem cell maintenance by fibroblast growth factor 4 requires MEKK4 activation of Jun N-terminal kinase. Mol Cell Biol. 2009;29:2748-61 pubmed publisher
    ..Our results define MEKK4 as a signaling hub for FGF4 activation of JNK that is required for maintenance of TS cells in an undifferentiated state. ..
  37. Takagaki K, Satoh T, Tanuma N, Masuda K, Takekawa M, Shima H, et al. Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and p38. Biochem J. 2004;383:447-55 pubmed
    ..4 M sorbitol. By screening with a variety of stimuli, we found that LDP-3 specifically enhances the osmotic stress-induced activation of JNK and p38. ..
  38. Halfter U, Derbyshire Z, Vaillancourt R. Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes. Biochem J. 2005;388:17-28 pubmed
    ..Furthermore, we provide evidence that SHP2 dephosphorylates MEKK4 and Pyk2, terminating the MEKK4-dependent branch of the IFNgamma signalling pathway. ..
  39. Akiyama S, Yonezawa T, Kudo T, Li M, Wang H, Ito M, et al. Activation mechanism of c-Jun amino-terminal kinase in the course of neural differentiation of P19 embryonic carcinoma cells. J Biol Chem. 2004;279:36616-20 pubmed
    ..These results suggest that two distinct TAK1-MKK4-JNK signaling pathways are independently activated at the different intracellular locations and may participate in the regulation of the neural differentiation of P19 cells. ..
  40. Ryabinina O, Subbian E, Iordanov M. D-MEKK1, the Drosophila orthologue of mammalian MEKK4/MTK1, and Hemipterous/D-MKK7 mediate the activation of D-JNK by cadmium and arsenite in Schneider cells. BMC Cell Biol. 2006;7:7 pubmed
    ..D-MEKK1, the fly orthologue of mammalian MEKK4/MTK1, and Hemipterous/D-MKK7 mediates the activation of D-JNK by cadmium and arsenite. ..
  41. Padda R, Wamsley Davis A, Gustin M, Ross R, Yu C, Sheikh Hamad D. MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells. Am J Physiol Renal Physiol. 2006;291:F874-81 pubmed
    ..Our data are consistent with the existence of an input from MEKK3 -->--> p38 kinase -->--> TonE. ..
  42. Sarkisian M, Bartley C, Rakic P. Trouble making the first move: interpreting arrested neuronal migration in the cerebral cortex. Trends Neurosci. 2008;31:54-61 pubmed publisher
    ..Elucidating the basic functions of FLNa and associated molecules is crucial for understanding the causes of PH and for developing prevention for at-risk patients. ..
  43. Delgado M. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. Biochem Biophys Res Commun. 2002;293:771-6 pubmed
    ..The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides. ..
  44. Jordan N, Johnson G, Abell A. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle. 2011;10:2865-73 pubmed
    ..This intersection between EMT and stemness in TS cells and claudin-low metastatic breast cancer demonstrates the usefulness of developmental EMT systems to understand EMT in cancer. ..
  45. Wei J, Chu C, Wang Y, Yang Y, Wang Q, Li T, et al. Association study of 45 candidate genes in nicotine dependence in Han Chinese. Addict Behav. 2012;37:622-6 pubmed publisher
    ..Furthermore, we for the first time report a significant association between nicotine dependence and DRD5, MAP3K4 and NPY1R. These findings need independent replication in the future studies. ..
  46. Chan Hui P, Weaver R. Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Biochem J. 1998;336 ( Pt 3):599-609 pubmed
    ..Differences in the reported functional activities of the three kinases are discussed. ..
  47. Sarkisian M, Siebzehnrubl D. Abnormal levels of Gadd45alpha in developing neocortex impair neurite outgrowth. PLoS ONE. 2012;7:e44207 pubmed publisher
  48. Suetsugu S, Takenawa T. Stress-associated MAP kinase fills in the map of filamin-mediated neuronal migration. Dev Cell. 2007;12:3-4 pubmed
  49. Ricote M, Royuela M, García Tuñón I, Bethencourt F, Paniagua R, Fraile B. Pro-apoptotic tumor necrosis factor-alpha transduction pathway in normal prostate, benign prostatic hyperplasia and prostatic carcinoma. J Urol. 2003;170:787-90 pubmed
    ..In prostate cancer this pathway is probably inactivated by other factors, such as p21 (at the ASK-1 level) or bcl-2 (at the JNK level). ..
  50. Lotan T, Lyon M, Huo D, Taxy J, Brendler C, Foster B, et al. Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. J Pathol. 2007;212:386-94 pubmed
    ..The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis. ..
  51. Kawahara A, Che Y, Hanaoka R, Takeda H, Dawid I. Zebrafish GADD45beta genes are involved in somite segmentation. Proc Natl Acad Sci U S A. 2005;102:361-6 pubmed
    ..These results indicate that regulated expression of gadd45beta genes in the anterior PSM is required for somite segmentation...
  52. Wong C, Luo W, Deng Y, Zou H, Ye Z, Lin S. The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms. J Biol Chem. 2004;279:39366-73 pubmed
  53. Liu H, Zhang H, Iles K, Rinna A, Merrill G, Yodoi J, et al. The ADP-stimulated NADPH oxidase activates the ASK-1/MKK4/JNK pathway in alveolar macrophages. Free Radic Res. 2006;40:865-74 pubmed