Gene Symbol: Map2k4
Description: mitogen-activated protein kinase kinase 4
Alias: JNKK1, MAPKK 4, MEK4, MKK4, PRKMK4, Sek1, Serk1, dual specificity mitogen-activated protein kinase kinase 4, C-JUN N-terminal kinase kinase 1, JNK kinase 1, JNK-activating kinase 1, MAP kinase kinase 4, MAPK/ERK kinase 4, SAPK/ERK kinase 1, SAPK/Erk/kinase 1, mitogen activated protein kinase kinase 4, variant 1
Species: mouse
Products:     Map2k4

Top Publications

  1. 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
    ..To identify downstream targets of MEKK4 during neural tube development, we examined the activity of MAP kinase kinase 4 (MKK4), a signaling intermediate between MAP kinase kinase kinase and JNK/p38...
  2. Brancho D, Tanaka N, Jaeschke A, Ventura J, Kelkar N, Tanaka Y, et al. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 2003;17:1969-78 pubmed
    The p38 mitogen-activated protein kinase (MAPK) is activated in vitro by three different protein kinases: MKK3, MKK4, and MKK6...
  3. Liu W, Zi M, Jin J, Prehar S, Oceandy D, Kimura T, et al. Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth. Circ Res. 2009;104:905-14 pubmed publisher
    ..pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown...
  4. Nishina H, Fischer K, Radvanyi L, Shahinian A, Hakem R, Rubie E, et al. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature. 1997;385:350-3 pubmed
    ..b>Sek1 (JNKK/MKK4) is a direct activator of SAPKs/JNKs in response to environmental stresses or mitogenic factors...
  5. Sanchez I, Hughes R, Mayer B, Yee K, Woodgett J, Avruch J, et al. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994;372:794-8 pubmed
    ..We have now identified a novel protein kinase, called SAPK/ERK kinase-1 (SEK1), which is structurally related to the MAP kinase kinases (MEKs)...
  6. Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, et al. JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol. 1999;19:7539-48 pubmed
    ..In similar cotransfection studies, JSAP1 also interacted with SEK1 MAPKK and MEKK1 MAPKKK, which are involved in the JNK cascades...
  7. Itoh T, Horiuchi M, Ikeda R, Xu J, Bannerman P, Pleasure D, et al. ZPK/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates. J Neurosci. 2014;34:10729-42 pubmed publisher
    ..kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in ..
  8. Maruyama T, Kadowaki H, Okamoto N, Nagai A, Naguro I, Matsuzawa A, et al. CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response. EMBO J. 2010;29:2501-14 pubmed publisher
    ..These findings show that transient activation of the ERK pathway, which depends not only on MEKK2 activation, but also on CHIP-dependent MEKK2 degradation, is crucial for proper gene expression in hyperosmotic stress response. ..
  9. Zi M, Kimura T, Liu W, Jin J, Higham J, Kharche S, et al. Mitogen-activated protein kinase kinase 4 deficiency in cardiomyocytes causes connexin 43 reduction and couples hypertrophic signals to ventricular arrhythmogenesis. J Biol Chem. 2011;286:17821-30 pubmed publisher

More Information


  1. Ahn Y, Yang Y, Gibbons D, Creighton C, Yang F, Wistuba I, et al. Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor ?2 expression. Mol Cell Biol. 2011;31:4270-85 pubmed publisher
    b>MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have ..
  2. Nishina H, Bachmann M, Oliveira Dos Santos A, Kozieradzki I, Fischer K, Odermatt B, et al. Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. J Exp Med. 1997;186:941-53 pubmed
    The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH2 terminal kinase [ JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, ..
  3. Ganiatsas S, Kwee L, Fujiwara Y, Perkins A, Ikeda T, Labow M, et al. SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc Natl Acad Sci U S A. 1998;95:6881-6 pubmed
    SEK1 (MKK4/JNKK) is a mitogen-activated protein kinase activator that has been shown to participate in vitro in two stress-activated cascades terminating with the SAPK and p38 kinases...
  4. Tu Z, Lee F. Subdomain VIII is a specificity-determining region in MEKK1. J Biol Chem. 2003;278:48498-505 pubmed
    ..Once activated, MEKK1 phosphorylates the MAP2K MKK4, which in turn phosphorylates JNK...
  5. Lim B, White R, Hummel G, Schwaeble W, Lynch N, Peerschke E, et al. Characterization of the murine gene of gC1qBP, a novel cell protein that binds the globular heads of C1q, vitronectin, high molecular weight kininogen and factor XII. Gene. 1998;209:229-37 pubmed
    ..The mouseC1qbp gene was mapped to chromosome 11, closely linked to D11Mit4 using genomic DNAs from a (C57BL/6J x Mus spretus)F1 x Mus spretus backcross. ..
  6. Swat W, Fujikawa K, Ganiatsas S, Yang D, Xavier R, Harris N, et al. SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development. Immunity. 1998;8:625-34 pubmed
    ..In lymphocytes, the SAPK pathway has been implicated in signaling from antigen, costimulatory, and death receptors; SEK1, which directly activates SAPK, is required for early embryonic development and has also been reported to be ..
  7. Szmulewitz R, Clark R, Lotan T, Otto K, Taylor Veneris J, Macleod K, et al. MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression. Int J Cancer. 2012;130:509-20 pubmed publisher
    ..b>Map kinase kinase 4 (MKK4) suppresses metastasis in a preclinical prostate cancer model...
  8. Li M, Katsura K, Nomiyama H, Komaki K, Ninomiya Tsuji J, Matsumoto K, et al. Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem. 2003;278:12013-21 pubmed
    ..of PP2Cepsilon inhibited the IL-1- and TAK1-induced activation of mitogen-activated protein kinase kinase 4 (MKK4)-c-Jun N-terminal kinase or MKK3-p38 signaling pathway. PP2Cepsilon dephosphorylated TAK1 in vitro...
  9. Tseng P, Matsuzawa A, Zhang W, Mino T, Vignali D, Karin M. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol. 2010;11:70-5 pubmed publisher
    ..Inhibition of degradative ubiquitination of TRAF3 prevented the expression of all proinflammatory cytokines without affecting the interferon response. ..
  10. Cazillis M, Bringuier A, Delautier D, Buisine M, Bernuau D, Gespach C, et al. Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. Oncogene. 2004;23:4735-44 pubmed
    The dual Ser/Thr kinase MKK4 and its downstream targets JNK and p38 regulate critical cellular functions during embryogenesis and development...
  11. Kinzig A, Heidt M, Furstenberger G, Marks F, Krieg P. cDNA cloning, genomic structure, and chromosomal localization of a novel murine epidermis-type lipoxygenase. Genomics. 1999;58:158-64 pubmed
    ..The novel lipoxygenase gene is divided into 15 exons and 14 introns, spanning 22.3 kb of genomic DNA. By interspecific backcross analysis, the novel gene was localized to the central region of mouse chromosome 11. ..
  12. Kelkar N, Delmotte M, Weston C, Barrett T, Sheppard B, Flavell R, et al. Morphogenesis of the telencephalic commissure requires scaffold protein JNK-interacting protein 3 (JIP3). Proc Natl Acad Sci U S A. 2003;100:9843-8 pubmed
    ..The central nervous system abnormalities of Jip3-/- mice may be accounted for in part by a reduction in signal transduction by RhoA and its effector ROCK. ..
  13. Mazzitelli S, Xu P, Ferrer I, Davis R, Tournier C. The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo. J Neurosci. 2011;31:16969-76 pubmed publisher
    ..Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD. ..
  14. Salmeron A, Ahmad T, Carlile G, Pappin D, Narsimhan R, Ley S. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J. 1996;15:817-26 pubmed
    ..Tpl-2, therefore, is a MAP kinase kinase kinase which can activate two MAP kinase pathways. After Raf and Mos, Tpl-2 is the third serine/threonine oncoprotein kinase that has been shown to function as a direct activator of MEK-1. ..
  15. Watanabe T, Nakagawa K, Ohata S, Kitagawa D, Nishitai G, Seo J, et al. SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti-apoptosis. Dev Biol. 2002;250:332-47 pubmed
    Mice lacking the stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12.5...
  16. 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. ..
  17. Lee D, Lee K, Byun S, Jung S, Song N, Lim S, et al. 7,3',4'-Trihydroxyisoflavone, a metabolite of the soy isoflavone daidzein, suppresses ultraviolet B-induced skin cancer by targeting Cot and MKK4. J Biol Chem. 2011;286:14246-56 pubmed publisher
    ..Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases...
  18. Pereira A, Leite F, Brasil B, Soares Martins J, Torres A, Pimenta P, et al. A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. J Virol. 2012;86:172-84 pubmed publisher
    ..leads to activation of the stress-activated protein kinase (SAPK)/extracellular signal-regulated kinase (ERK) 4/7 (MKK4/7)-c-Jun N-terminal protein kinase 1/2 (JNK1/2) pathway; further, the stimulation of this pathway requires ..
  19. Zhang C, Kenski D, Paulson J, Bonshtien A, Sessa G, Cross J, et al. A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases. Nat Methods. 2005;2:435-41 pubmed
    ..The ability to identify second-site suppressors to rescue the activity of intolerant kinases should facilitate chemical genetic analysis of the majority of protein kinases in the genome. ..
  20. Kishimoto H, Nakagawa K, Watanabe T, Kitagawa D, Momose H, Seo J, et al. Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells. J Biol Chem. 2003;278:16595-601 pubmed
    ..SAPK/JNK activation requires the phosphorylation of both Thr and Tyr residues in its Thr-Pro-Tyr motif, and SEK1 and MKK7 have been identified as the dual specificity kinases...
  21. Krieg P, Siebert M, Kinzig A, Bettenhausen R, Marks F, Furstenberger G. Murine 12(R)-lipoxygenase: functional expression, genomic structure and chromosomal localization. FEBS Lett. 1999;446:142-8 pubmed
    ..5 kb. By interspecific backcross analysis, the 12(R)-lipoxygenase gene was localized to the central region of mouse chromosome 11. ..
  22. Peng Z, Peng L, Fan Y, Zandi E, Shertzer H, Xia Y. A critical role for IkappaB kinase beta in metallothionein-1 expression and protection against arsenic toxicity. J Biol Chem. 2007;282:21487-96 pubmed
    ..a marked increase in arsenic-induced reactive oxygen species (ROS) accumulation, which leads to activation of the MKK4-c-Jun NH(2)-terminal kinase (JNK) pathway, c-Jun phosphorylation, and apoptosis...
  23. Nakajima A, Komazawa Sakon S, Takekawa M, Sasazuki T, Yeh W, Yagita H, et al. An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J. 2006;25:5549-59 pubmed
    ..Taken that ROS promote JNK activation and activation of the JNK pathway may promote ROS accumulation, c-FLIPL might block this positive feedback loop, thereby suppressing ROS accumulation. ..
  24. Vernia S, Cavanagh Kyros J, Barrett T, Tournier C, Davis R. Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK. Cell Rep. 2016;14:2273-80 pubmed publisher
    ..Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome. ..
  25. Su Y, Han J, Xu S, Cobb M, Skolnik E. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J. 1997;16:1279-90 pubmed
    ..These findings indicate that the C-terminal domain of these proteins encodes a new protein domain family and suggests that this domain couples these kinases to the SAPK pathway, possibly by interacting with MEKK1 or related kinases. ..
  26. Finegan K, Tournier C. The mitogen-activated protein kinase kinase 4 has a pro-oncogenic role in skin cancer. Cancer Res. 2010;70:5797-806 pubmed publisher
    The mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a nonredundant component of stress-activated MAPK signaling modules...
  27. Hübner A, Mulholland D, Standen C, Karasarides M, Cavanagh Kyros J, Barrett T, et al. JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate. Proc Natl Acad Sci U S A. 2012;109:12046-51 pubmed publisher
    ..Similarly, prevention of JNK activation in the prostate epithelium (?Mkk4 ?Mkk7 ?Pten mice) causes rapid development of invasive adenocarcinoma...
  28. Yamasaki T, Kawasaki H, Arakawa S, Shimizu K, Shimizu S, Reiner O, et al. Stress-activated protein kinase MKK7 regulates axon elongation in the developing cerebral cortex. J Neurosci. 2011;31:16872-83 pubmed publisher
    ..JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 7 and MKK4. To elucidate the physiological functions of MKK7, we used Nestin-Cre to generate a novel mouse model in which the ..
  29. Jaeschke A, Davis R. Metabolic stress signaling mediated by mixed-lineage kinases. Mol Cell. 2007;27:498-508 pubmed
    ..of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FFA-stimulated JNK activation...
  30. Ahn Y, Kurie J. MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch. J Biol Chem. 2009;284:29399-404 pubmed publisher
    ..Here, we investigated the signals that negatively regulate MKK4/SEK1, an upstream activator of the MAPKs JNK and p38/HOG1...
  31. Valk P, Verbakel S, von Lindern M, Lowenberg B, Delwel R. Enhancement of erythropoietin-stimulated cell proliferation by Anandamide correlates with increased activation of the mitogen-activated protein kinases ERK1 and ERK2. Hematol J. 2000;1:254-63 pubmed
  32. Davies L, Jin J, Shen W, Tsui H, Shi Y, Wang Y, et al. Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age. J Am Heart Assoc. 2014;3:e000340 pubmed publisher
    ..In the present study, we explored the role of mitogen-activated protein kinase kinase 4 (Mkk4), a critical component of the stress-activated mitogen-activated protein kinase family, in age-associated AF...
  33. Kim J, Kim E, Kim H, Kurie J, Ahn Y. MKK4 activates non-canonical NF?B signaling by promoting NF?B2-p100 processing. Biochem Biophys Res Commun. 2017;491:337-342 pubmed publisher
    ..Here, we found that NF?B2 processing and activation were mediated by mitogen-activated protein kinase kinase-4 (MKK4) and its substrate c-Jun N-terminal kinase (JNK)...
  34. 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
    ..Whereas Aida-MO injection leads to dorsalized embryos, JNK-MO and MKK4-MO can ventralize embryos...
  35. Huang Z, Zhang K, Chen X, Meng J, Chen D. Effect of siRNA targeted against MKK4 on myostatin-induced downregulation of differentiation marker gene expression. Mol Cell Biochem. 2008;310:241-4 pubmed
    The c-Jun N-terminal kinase (JNK) pathway was reported to be involved in myostatin signaling and MKK4 was suggested as the only upstream kinase for myostatin-induced JNK activation, implying that MKK4 is a suitable target of RNA ..
  36. Yang P, Zhao Z, Reece E. Involvement of c-Jun N-terminal kinases activation in diabetic embryopathy. Biochem Biophys Res Commun. 2007;357:749-54 pubmed
    ..Phosphorylated SEK1 were significantly elevated in malformed embryos from diabetic mouse...
  37. Brint E, Fitzgerald K, Smith P, Coyle A, Gutierrez Ramos J, Fallon P, et al. Characterization of signaling pathways activated by the interleukin 1 (IL-1) receptor homologue T1/ST2. A role for Jun N-terminal kinase in IL-4 induction. J Biol Chem. 2002;277:49205-11 pubmed
  38. Zhang L, Zhou M, Wang Y, Huang W, Qin G, Weintraub N, et al. miR-92a inhibits vascular smooth muscle cell apoptosis: role of the MKK4-JNK pathway. Apoptosis. 2014;19:975-83 pubmed publisher
    ..assay, we found that miR-92a overexpression led to suppression of both mitogen-activated protein kinase kinase 4 (MKK4)- and JNK1-dependent luciferase activity...
  39. Srivastava R, Burbach B, Mitchell J, Pagán A, Shimizu Y. ADAP regulates cell cycle progression of T cells via control of cyclin E and Cdk2 expression through two distinct CARMA1-dependent signaling pathways. Mol Cell Biol. 2012;32:1908-17 pubmed publisher
    ..Thus, ADAP coordinates distinct CARMA1-dependent control of key cell cycle proteins in T cells. ..
  40. Wang J, Chen L, Ko C, Zhang L, Puga A, Xia Y. Distinct signaling properties of mitogen-activated protein kinase kinases 4 (MKK4) and 7 (MKK7) in embryonic stem cell (ESC) differentiation. J Biol Chem. 2012;287:2787-97 pubmed publisher
    ..b>MKK4 and MKK7 are upstream kinases of the mitogen-activated protein kinases (MAPKs), responsible for channeling ..
  41. Fong B, Watson P, Watson A. Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation. BMC Dev Biol. 2007;7:2 pubmed
    ..Our results indicate that Ccm2 along with upstream p38 MAPK pathway constituents (Map3k3, Map2k3, Map2k6, and Map2k4) are expressed throughout mouse preimplantation development...
  42. Lai L, Song Y, Liu Y, Chen Q, Han Q, Chen W, et al. MicroRNA-92a negatively regulates Toll-like receptor (TLR)-triggered inflammatory response in macrophages by targeting MKK4 kinase. J Biol Chem. 2013;288:7956-67 pubmed publisher
    ..Furthermore, mitogen-activated protein kinase kinase 4 (MKK4), a kinase that activates JNK/stress-activated protein kinase, was found to be directly targeted by miR-92a...
  43. Kim M, Chae J, Kim K, Hwang S, Yoon K, Kim E, et al. Negative regulation of SEK1 signaling by serum- and glucocorticoid-inducible protein kinase 1. EMBO J. 2007;26:3075-85 pubmed
    ..We have now shown that SGK1 inhibits the activation of SEK1 and thereby negatively regulates the JNK signaling pathway...
  44. Nishina H, Vaz C, Billia P, Nghiem M, Sasaki T, de la Pompa J, et al. Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development. 1999;126:505-16 pubmed
    The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in response to a variety of cellular stresses, such as changes in osmolarity, metabolic ..
  45. Bulat N, Waeber G, Widmann C. LDLs stimulate p38 MAPKs and wound healing through SR-BI independently of Ras and PI3 kinase. J Lipid Res. 2009;50:81-9 pubmed publisher
    ..Here we show that MAPK kinases MKK3 and MKK6, but not MKK4, are the upstream kinases responsible for the activation of the p38 MAPKs and stimulation of wound closure in ..
  46. Osugi T, Ding Y, Tanaka H, Kuo C, Do E, Irie Y, et al. Involvement of a single-stranded DNA binding protein, ssCRE-BP/Pur alpha, in morphine dependence. FEBS Lett. 1996;391:11-6 pubmed
    ..The levels of ssCRE-BP/Pur alpha and the transcript were not changed by chronic morphine treatment, however, the levels of an activator of ssCRE-BP/Pur alpha, which is necessary for the DNA binding, may be modulated by the treatment. ..
  47. Yang D, Tournier C, Wysk M, Lu H, Xu J, Davis R, et al. Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity. Proc Natl Acad Sci U S A. 1997;94:3004-9 pubmed
    b>MKK4 is a member of the mitogen-activated protein kinase kinase group of dual specificity protein kinases that functions as an activator of the c-Jun NH2-terminal kinase (JNK) in vitro...
  48. Oki T, Yamazaki K, Kuromitsu J, Okada M, Tanaka I. cDNA cloning and mapping of a novel subtype of glutamine:fructose-6-phosphate amidotransferase (GFAT2) in human and mouse. Genomics. 1999;57:227-34 pubmed
    ..GFAT2 can provide insights into understanding the roles of the hexosamine pathway in various tissues, particularly with the development of glucose toxicity and diabetes complications. ..
  49. Lee J, Hwang W, Lee Y, Han P. Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice. Brain Res Mol Brain Res. 1999;66:133-40 pubmed
    ..It is well established that SAPK/JNK activation is controlled by SEK1/MKK4, an up-stream MAP kinase kinase...
  50. Tournier C, Whitmarsh A, Cavanagh J, Barrett T, Davis R. The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Mol Cell Biol. 1999;19:1569-81 pubmed
    ..Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators...
  51. Nishina H, Radvanyi L, Raju K, Sasaki T, Kozieradzki I, Penninger J. Impaired TCR-mediated apoptosis and Bcl-XL expression in T cells lacking the stress kinase activator SEK1/MKK4. J Immunol. 1998;161:3416-20 pubmed
    The dual specificity kinase SEK1 (MKK4) is a direct activator of stress-activated protein kinases (SAPK/JNK) in response to environmental stresses or mitogenic factors...
  52. Welsbie D, Mitchell K, Jaskula Ranga V, Sluch V, Yang Z, Kim J, et al. Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons. Neuron. 2017;94:1142-1154.e6 pubmed publisher
    ..Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. ..
  53. Wuestefeld T, Pesic M, Rudalska R, Dauch D, Longerich T, Kang T, et al. A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell. 2013;153:389-401 pubmed publisher
    ..Our studies identify the dual-specific kinase MKK4 as a master regulator of liver regeneration...
  54. Davies C, Harvey E, McMahon R, Finegan K, Connor F, Davis R, et al. Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma. Cancer Res. 2014;74:3344-56 pubmed publisher
    ..protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC)...
  55. 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
    ..Moreover, we describe experiments showing the presence of activated MKK4, a direct target of MAP3K4, and activated p38 in the coelomic region of the XY gonad at 11...
  56. Lee C, Onesime D, Reddy C, Dhanasekaran N, Reddy E. JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. Proc Natl Acad Sci U S A. 2002;99:14189-94 pubmed
    ..together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3)...
  57. Xia D, Srinivas H, Ahn Y, Sethi G, Sheng X, Yung W, et al. Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NF kappa B-dependent pathway. J Biol Chem. 2007;282:3507-19 pubmed
    Mitogen-activated protein kinase kinase-4 (MKK4/SEK1) cooperates with phosphatidylinositol 3-kinase to maintain the survival of non-small cell lung cancer (NSCLC) cells, but the biochemical basis of this phenomenon has not been elucidated...
  58. Yang J, New L, Jiang Y, Han J, Su B. Molecular cloning and characterization of a human protein kinase that specifically activates c-Jun N-terminal kinase. Gene. 1998;212:95-102 pubmed
    ..through dual phosphorylation of a theronine residue and a tyrosine residue by a dual specificity kinase such as JNKK1/MKK4/SEK1...
  59. Zou H, Li Q, Lin S, Wu Z, Han J, Ye Z. Differential requirement of MKK4 and MKK7 in JNK activation by distinct scaffold proteins. FEBS Lett. 2007;581:196-202 pubmed
    ..Here, using MKK4(-/-) and MKK4(-/-)/7(-/-) murine embryonic fibroblast cells, we examined differential employment of MKK4 and MKK7 ..
  60. Zhang J, Min R, Le K, Zhou S, Aghajan M, Than T, et al. The role of MAP2 kinases and p38 kinase in acute murine liver injury models. Cell Death Dis. 2017;8:e2903 pubmed publisher
    ..Downstream of MAP3K, in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK...
  61. Nishitai G, Matsuoka M. Differential regulation of HSP70 expression by the JNK kinases SEK1 and MKK7 in mouse embryonic stem cells treated with cadmium. J Cell Biochem. 2008;104:1771-80 pubmed publisher
    JNK, a member of the mitogen-activated protein kinases (MAPKs), is activated by the MAPK kinases SEK1 and MKK7 in response to environmental stresses...
  62. 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
    ..In this study, we demonstrated that activities of MAPK kinase 4 (MKK4) and TAK1, one of the upstream kinases of MKK4, were enhanced in the neurally differentiating cells...
  63. Haeusgen W, Tueffers L, Herdegen T, Waetzig V. Map2k4? - identification and functional characterization of a novel Map2k4 splice variant. Biochim Biophys Acta. 2014;1843:875-84 pubmed publisher
    Mitogen-activated protein kinase kinase 4 (Map2k4) is a dual specificity serin/threonine protein kinase that is unique among all MAP2Ks in activating two different subfamilies of mitogen-activated protein kinases, the c-Jun N-terminal ..
  64. White R, Hughes R, Adkison L, Bruns G, Zon L. The gene encoding protein kinase SEK1 maps to mouse chromosome 11 and human chromosome 17. Genomics. 1996;34:430-2 pubmed
    ..The human SERK1 gene was assigned to human chromosome 17 using genomic DNAs from human-rodent somatic cell hybrid lines...