Gene Symbol: Map3k4
Description: mitogen-activated protein kinase kinase kinase 4
Alias: D17Rp17, D17Rp17e, MAPKKK4, MEKK 4, MTK1, Mek4b, Mekk4, RP17, Rp17a, Tas, mKIAA0213, mitogen-activated protein kinase kinase kinase 4, MAPK/ERK kinase kinase 4, MEK kinase 4, T-associated sex reversal
Species: mouse
Products:     Map3k4

Top Publications

  1. Washburn L, Albrecht K, Eicher E. C57BL/6J-T-associated sex reversal in mice is caused by reduced expression of a Mus domesticus Sry allele. Genetics. 2001;158:1675-81 pubmed
    C57BL/6J-T-associated sex reversal (B6-TAS) in XY mice results in ovarian development and involves (1) hemizygosity for Tas, a gene located in the region of Chromosome 17 deleted in T(hp) and T(Orl), (2) homozygosity for one or more B6-..
  2. Craig E, Stevens M, Vaillancourt R, Camenisch T. MAP3Ks as central regulators of cell fate during development. Dev Dyn. 2008;237:3102-14 pubmed publisher
    ..This perspective reveals that some of these MAP3K effectors may have redundant functions, and also serve as unique nexus depending on the context of the signaling pathway. ..
  3. 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...
  4. 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
    Loss of the kinase MAP3K4 causes mouse embryonic gonadal sex reversal due to reduced expression of the testis-determining gene, Sry...
  5. Gerwins P, Blank J, Johnson G. Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J Biol Chem. 1997;272:8288-95 pubmed
    ..We have isolated two cDNAs encoding splice variants of a novel MEK kinase, MEKK4. The MEKK4 mRNA is widely expressed in mouse tissues and encodes for a protein of approximately 180 kDa...
  6. 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
    ..Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R))...
  7. 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
    ..We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT)...
  8. Washburn L, Eicher E. Normal testis determination in the mouse depends on genetic interaction of a locus on chromosome 17 and the Y chromosome. Genetics. 1989;123:173-9 pubmed
    ..This locus was designated "T-associated sex reversal" (Tas) because it segregated with the dominant brachyury allele hairpin tail (Thp) and caused gonads of C57BL/6J XY, Thp/+..
  9. Warr N, Bogani D, Siggers P, Brixey R, Tateossian H, Dopplapudi A, et al. Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1. PLoS ONE. 2011;6:e19572 pubmed publisher
    ..Based on these observations, we conclude that MAP3K1 is not required for mouse testis determination. We discuss the significance of these data for the functional interpretation of sex-reversing MAP3K1 mutations in humans. ..

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
    ..However, how GADD45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with GADD45 in vitro...
  2. 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
    ..The byg mutation is an A to T transversion causing a premature stop codon in the gene encoding MAP3K4 (also known as MEKK4), a mitogen-activated protein kinase kinase kinase. Analysis of XY byg/byg gonads at 11...
  3. Mann E, Silver L, Elliott R. Genetic analysis of a mouse t complex locus that is homologous to a kidney cDNA clone. Genetics. 1986;114:993-1006 pubmed
    ..One, designated D17Rp17, has been mapped near quaking, (qk), on chromosome 17 using three sets of recombinant inbred (RI) strains...
  4. Washburn L, Eicher E. Sex reversal in XY mice caused by dominant mutation on chromosome 17. Nature. 1983;303:338-40 pubmed
    ..This dominantly inherited trait, tentatively named T-associated sex reversal (gene symbol Tas), is closely linked to or a part of the T/t complex on chromosome 17 of the mouse...
  5. Washburn L, Lee B, Eicher E. Inheritance of T-associated sex reversal in mice. Genet Res. 1990;56:185-91 pubmed
    We previously identified a primary sex-determining locus, Tas, on mouse Chr 17 that causes ovarian tissue development in C57BL/6J Thp/+ and TOrl/+ individuals if the AKR/JY chromosome is present...
  6. Gregorova S, Mnuková Fajdelová M, Trachtulec Z, Capkova J, Loudova M, Hoglund M, et al. Sub-milliMorgan map of the proximal part of mouse Chromosome 17 including the hybrid sterility 1 gene. Mamm Genome. 1996;7:107-13 pubmed
    ..The submilliMorgan map of the T-H2 region revealed significant clustering of (CA)n loci. The clustering, if shown to be a common feature in the mouse genome, may cause gaps in the physical map of the mouse genome. ..
  7. Schweifer N, Valk P, Delwel R, Cox R, Francis F, Meier Ewert S, et al. Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene. Genomics. 1997;43:285-97 pubmed
    ..The remaining genes in this region have previously been shown to be biallelically expressed. ..
  8. King T, Dove W. Pleiotropic action of the murine quaking locus: structure of the qkv allele. Mamm Genome. 1991;1:47-52 pubmed
    ..This variability of two-factor map values leads to the preferred multilocus map-building protocol discussed in the accompanying paper...
  9. Bullard S, Seo S, Schilling B, Dyle M, Dierdorff J, Ebert S, et al. Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4. J Biol Chem. 2016;291:17496-17509 pubmed publisher
    ..We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle ..
  10. Rui Y, Xu Z, Xiong B, Cao Y, Lin S, Zhang M, et al. A beta-catenin-independent dorsalization pathway activated by Axin/JNK signaling and antagonized by aida. Dev Cell. 2007;13:268-82 pubmed
    ..We have thus identified a dorsalization pathway that is exerted by Axin/JNK signaling and its inhibitor Aida during vertebrate embryogenesis. ..
  11. Andrechek E, Mori S, Rempel R, Chang J, Nevins J. Patterns of cell signaling pathway activation that characterize mammary development. Development. 2008;135:2403-13 pubmed publisher
    ..Taken together, these results reveal a complex pattern of pathway activity in relation to the various phases of mammary gland development. ..
  12. Degen S, Bell S, Schaefer L, Elliott R. Characterization of the cDNA coding for mouse plasminogen and localization of the gene to mouse chromosome 17. Genomics. 1990;8:49-61 pubmed
    ..has allowed the localization of the mouse plasminogen gene to the proximal end of mouse chromosome 17 within the t complex and close to the locus D17Rp17. The Plg gene is deleted in the semidominant deletion mutant, hair-pintail (Thp).
  13. Bikkavilli R, Feigin M, Malbon C. G alpha o mediates WNT-JNK signaling through dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells. J Cell Sci. 2008;121:234-45 pubmed publisher
    ..Activation of the small GTPases RhoA, Rac1 and Cdc42 operates downstream of Dishevelled, linking to the MEKK 1/MEKK 4-dependent cascade, and on to JNK activation...
  14. 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
    ..Here, we show that the MEKK4 (MAP3K4) pathway is involved in Fln-A regulation and PVH formation...
  15. Stevens M, Parker P, Vaillancourt R, Camenisch T. MEKK4 regulates developmental EMT in the embryonic heart. Dev Dyn. 2006;235:2761-70 pubmed
    ..The cytoplasmic MAP kinase kinase kinase, MEKK4, is a critical effector in cellular stress responses; however, the function of MEKK4 during embryonic development ..
  16. Herrmann B, Bucan M, Mains P, Frischauf A, Silver L, Lehrach H. Genetic analysis of the proximal portion of the mouse t complex: evidence for a second inversion within t haplotypes. Cell. 1986;44:469-76 pubmed
    ..This newly described proximal inversion and the previously described distal inversion provide an explanation for the suppression of recombination observed along the length of t haplotype DNA in heterozygous mice. ..
  17. 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
    ..In our present study, we have shown that another MEKK family member, MEKK4, also binds to Axin in vivo and mediates Axin-induced JNK activation...
  18. Warr N, Siggers P, Carré G, Bogani D, Brixey R, Akiyoshi M, et al. Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice. Hum Mol Genet. 2014;23:3035-44 pubmed publisher
    ..We recently reported that mice heterozygous for a null allele of Map3k4, which resides in the T(hp) deletion, exhibit XY ovotestis development and occasional gonadal sex reversal on the ..
  19. Balliet A, Hollander M, Fornace A, Hoffman B, Liebermann D. Comparative analysis of the genetic structure and chromosomal mapping of the murine Gadd45g/CR6 gene. DNA Cell Biol. 2003;22:457-68 pubmed
    ..critical cell cycle and cell survival regulatory proteins such as PCNA, p21(WAF1/CIP1), CDK1 (cdc2-p34), and MTK1/MEKK4, and have been reported to influence the activity of the p38 and JNK kinases...
  20. McLachlan S, Lee S, Steele T, Hawthorne P, Zapala M, Eskin E, et al. In silico QTL mapping of basal liver iron levels in inbred mouse strains. Physiol Genomics. 2011;43:136-47 pubmed publisher
    ..32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies. ..
  21. Nadeau J, Herrmann B, Bucan M, Burkart D, Crosby J, Erhart M, et al. Genetic maps of mouse chromosome 17 including 12 new anonymous DNA loci and 25 anchor loci. Genomics. 1991;9:78-89 pubmed
  22. 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
    ..We report the identification of a human MAPK kinase kinase, MAPKKK4, via sequence similarity with other MAPKKKs...
  23. Gao J, Chen H, Filie J, Kozak C, Murphy P. Differential expansion of the N-formylpeptide receptor gene cluster in human and mouse. Genomics. 1998;51:270-6 pubmed
    ..These results suggest that the FPR gene cluster has undergone differential expansion in mammals with FPRL2, Fpr-rs2, Fpr-rs3, Fpr-rs4, and Fpr-rs5 arising after divergence of human and mouse. ..
  24. 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
    The MAPK kinase kinase MEKK4 is required for neurulation and skeletal patterning during mouse development. MEKK4 phosphorylates and activates MKK4/MKK7 and MKK3/MKK6 leading to the activation of JNK and p38, respectively...
  25. Cox R, Whittington J, Shedlovsky A, Connelly C, Dove W, Goldsworthy M, et al. Detailed physical and genetic mapping in the region of plasminogen, D17Rp17e, and quaking. Mamm Genome. 1993;4:687-94 pubmed a detailed physical map encompassing over 600 kb of mouse Chromosome (Chr) 17 in the region of plasminogen, D17Rp17e, and quaking. This region is cloned in yeast artificial chromosomes (YACs)...
  26. 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
    ..Mice harboring a point mutation that renders inactive the mitogen-activated protein kinase kinase kinase MEKK4 exhibit dysregulated placental development with increased trophoblast invasion...
  27. 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
    MTK1 (MEKK4) is a mitogen-activated protein kinase kinase kinase that regulates the activity of its downstream mitogen-activated kinases, p38, and c-Jun N-terminal kinase (JNK)...
  28. King T, Dove W, Guenet J, Herrmann B, Shedlovsky A. Meiotic mapping of murine chromosome 17: the string of loci around l(17)-2Pas. Mamm Genome. 1991;1:37-46 pubmed
    ..Robust genetic maps can be constructed with multilocus crosses that share anchor loci. DNA markers can be interpolated onto these maps retrospectively. ..
  29. Fanger G, Johnson N, Johnson G. MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. EMBO J. 1997;16:4961-72 pubmed
    ..Differential MEKK subcellular distribution and interaction with small GTP-binding proteins provides a mechanism to regulate MAP kinase responses in localized regions of the cell and to different upstream stimuli. ..
  30. Forejt J, Vincek V, Klein J, Lehrach H, Loudová Micková M. Genetic mapping of the t-complex region on mouse chromosome 17 including the Hybrid sterility-1 gene. Mamm Genome. 1991;1:84-91 pubmed
    ..The limit of resolution of the cross was 0.27 cM. The map distances have been determined for the DNA loci in the T-H-2 interval and the Hst-1 gene was mapped in close vicinity to the D17Rp17 locus.
  31. Sarvetnick N, Tsai J, Fox H, Pilder S, Silver L. A mouse chromosome 17 gene encodes a testes-specific transcript with unusual properties. Immunogenetics. 1989;30:34-41 pubmed
    ..Although a function for D17Si11 has yet to be determined, the gene is relatively nonpolymorphic in mice and appears conserved in mammals. ..
  32. Abell A, Johnson G. MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J Biol Chem. 2005;280:35793-6 pubmed
    ..Here, we show that endogenous TRAF4 and MEKK4 associate in both human K562 cells and mouse E10.5 embryos. TRAF4 interacts with the kinase domain of MEKK4...
  33. Haque K, Pandey A, Zheng H, Riazuddin S, Sha S, Puligilla C. MEKK4 Signaling Regulates Sensory Cell Development and Function in the Mouse Inner Ear. J Neurosci. 2016;36:1347-61 pubmed publisher
    ..Here, we show that mitogen-activated protein 3 kinase 4 (MEKK4) expression is highly regulated during inner ear development and is critical to normal cytoarchitecture and ..
  34. Himmelbauer H, Silver L. High-resolution comparative mapping of mouse chromosome 17. Genomics. 1993;17:110-20 pubmed
    ..We present the localization of four new DNA markers and determined map positions for 10 other loci, which previously had been assigned to intervals of the t complex only through the study of partial t haplotype chromosomes. ..
  35. Park E, Principato M, Lamers M, Dickler H. Ly-39: a new lymphocyte alloantigen defined with a monoclonal antibody. Immunogenetics. 1988;28:64-6 pubmed
  36. Fujimoto Y, Tanaka S, Yamaguchi Y, Kobayashi H, Kuroki S, Tachibana M, et al. Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Dev Cell. 2013;26:416-30 pubmed publisher
    ..The regulation of Fog2 induces Sry expression in male sex determination, and the regulation of Nr5a1 in gonadal precursor formation determines gonadal size. ..
  37. Lu Z, Liu W, Huang H, He Y, Han Y, Rui Y, et al. Protein encoded by the Axin(Fu) allele effectively down-regulates Wnt signaling but exerts a dominant negative effect on c-Jun N-terminal kinase signaling. J Biol Chem. 2008;283:13132-9 pubmed publisher
  38. Hemmerich P, von Mikecz A, Neumann F, Sozeri O, Wolff Vorbeck G, Zoebelein R, et al. Structural and functional properties of ribosomal protein L7 from humans and rodents. Nucleic Acids Res. 1993;21:223-31 pubmed
    ..We show here that the region of L7 carrying the latter motif mediates L7-dimerization and stable binding to DNA and RNA. A preferential binding to RNA-structures is demonstrated. ..
  39. Planchart A, You Y, Schimenti J. Physical mapping of male fertility and meiotic drive quantitative trait loci in the mouse t complex using chromosome deficiencies. Genetics. 2000;155:803-12 pubmed
    ..We present evidence for the existence of multiple proximal t complex regions that exhibit distorter activity. These studies demonstrate the utility of chromosome deletions for complex trait analysis. ..
  40. Mizuno K, Vincek V, Figueroa F, Klein J. The D17Tu5 locus in the t complex: implications for the origin of t haplotypes and inbred strains. Immunogenetics. 1989;30:105-11 pubmed
    ..inbred strains and partial t haplotypes, the D17Tu5 locus could be mapped to a position between the D17Leh66E and D17Rp17 loci within the t complex...
  41. King T, Dove W, Herrmann B, Moser A, Shedlovsky A. Mapping to molecular resolution in the T to H-2 region of the mouse genome with a nested set of meiotic recombinants. Proc Natl Acad Sci U S A. 1989;86:222-6 pubmed
    ..This set of DNA samples has been used to map the molecular marker D17RP17 just distal of quaking(lethal-1)...
  42. Barlow D, Stöger R, Herrmann B, Saito K, Schweifer N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature. 1991;349:84-7 pubmed
    ..We also demonstrate that embryos express Igf2r only from the maternal chromosome, and that Tcp-1, Plg and Sod-2 are expressed from both chromosomes. Therefore Igf2r is imprinted and closely linked or identical to Tme. ..
  43. Li X, Masinde G, Gu W, Wergedal J, Mohan S, Baylink D. Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 Mice: single QTL effects, epistasis, and pleiotropy. Genomics. 2002;79:734-40 pubmed
    ..Identification of the genes unique to FBS may have an impact on prediction of osteoporosis in human. ..
  44. Warr N, Siggers P, Carré G, Wells S, Greenfield A. Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination. Biol Reprod. 2016;94:103 pubmed publisher
    ..for mitogen-activated protein kinase (MAPK) signaling in testis determination: targeted loss of the kinases MAP3K4 and p38 MAPK causes complete XY embryonic gonadal sex reversal...
  45. Mobley R, Raghu D, Duke L, Abell Hart K, Zawistowski J, Lutz K, et al. MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition. Cell Rep. 2017;18:2387-2400 pubmed publisher
    ..Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TSKI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose ..