Gene Symbol: MKK4
Description: mitogen-activated protein kinase kinase 4
Alias: JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1, SEK1, SERK1, SKK1, dual specificity mitogen-activated protein kinase kinase 4, JNK-activated kinase 1, JNK-activating kinase 1, MAP kinase kinase 4, MAPK/ERK kinase 4, MAPKK 4, MEK 4, SAPK/ERK kinase 1, c-Jun N-terminal kinase kinase 1, stress-activated protein kinase kinase 1
Species: human
Products:     MKK4

Top Publications

  1. Derijard B, Raingeaud J, Barrett T, Wu I, Han J, Ulevitch R, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267:682-5 pubmed
    ..Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase...
  2. Su G, Hilgers W, Shekher M, Tang D, Yeo C, Hruban R, et al. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 1998;58:2339-42 pubmed
    Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins...
  3. Fleming Y, Armstrong C, Morrice N, Paterson A, Goedert M, Cohen P. Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Biochem J. 2000;352 Pt 1:145-54 pubmed
    ..Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine ..
  4. Kim H, Vander Griend D, Yang X, Benson D, Dubauskas Z, Yoshida B, et al. Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res. 2001;61:2833-7 pubmed
    ..A. Yoshida et al., Cancer Res., 59: 5483-5487) that mitogen-activated protein kinase kinase 4 (MKK4) can suppress AT6.1 rat prostate cancer metastases in vivo...
  5. Nakayama K, Nakayama N, Davidson B, Katabuchi H, Kurman R, Velculescu V, et al. Homozygous deletion of MKK4 in ovarian serous carcinoma. Cancer Biol Ther. 2006;5:630-4 pubmed
    ..4 Mb which harbored a candidate tumor suppressor gene, mitogen-activated protein kinase kinase-4 (MKK4)...
  6. 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...
  7. Xu L, Ding Y, Catalona W, Yang X, Anderson W, Jovanovic B, et al. MEK4 function, genistein treatment, and invasion of human prostate cancer cells. J Natl Cancer Inst. 2009;101:1141-55 pubmed publisher
    ..All cell lines were transiently transfected with a constitutively active mitogen-activated protein kinase kinase 4 (MEK4) expression vector (to increase MEK4 expression), small interfering RNA against MEK4 (to decrease MEK4 expression), ..
  8. Ishikawa M, Nakayama K, Rahman M, Rahman M, Katagiri A, Iida K, et al. Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer. Oncology. 2010;79:238-46 pubmed publisher
    ..current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase-4 (MKK4) expression to the development of endometrial cancer...
  9. Yeasmin S, Nakayama K, Rahman M, Rahman M, Ishikawa M, Katagiri A, et al. MKK4 acts as a potential tumor suppressor in ovarian cancer. Tumour Biol. 2011;32:661-70 pubmed publisher
    Our previous studies indicate that loss of MKK4 expression is associated with the progression of ovarian cancer. However, direct evidence that MKK4 inhibits the malignant phenotype of ovarian cancer cells is limited...

More Information

Publications129 found, 100 shown here

  1. Teng D, Perry W, Hogan J, Baumgard M, Bell R, Berry S, et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 1997;57:4177-82 pubmed
    ..A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-..
  2. 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...
  3. Park H, Kim M, Huh S, Park J, Chung J, Kang S, et al. Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J Biol Chem. 2002;277:2573-8 pubmed
    ..Here we report that SEK1 is a target of Akt in intact cells...
  4. Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, et al. Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade. J Biol Chem. 2002;277:40703-9 pubmed
    ..ASK1 phosphorylated JSAP1 in vitro and in vivo, and the phosphorylation facilitated interactions of JSAP1 with SEK1/MKK4, MKK7 and JNK3...
  5. Tassi E, Lai E, Li L, Solis G, Chen Y, Kietzman W, et al. Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor-Binding Protein). Hypertension. 2018;71:160-167 pubmed publisher
    ..analysis of kidney tissues after BP1 induction show that MAPK (mitogen-activated protein kinase) signaling via MKK4 (MAPK kinase 4), p38, and JNK (c-Jun N-terminal kinase) integrates the crosstalk of the FGF receptor and AngII ..
  6. Yin J, Li H, Meng C, Chen D, Chen Z, Wang Y, et al. Inhibitory effects of omega-3 fatty acids on early brain injury after subarachnoid hemorrhage in rats: Possible involvement of G protein-coupled receptor 120/?-arrestin2/TGF-? activated kinase-1 binding protein-1 signaling pathway. Int J Biochem Cell Biol. 2016;75:11-22 pubmed publisher fatty acids could inhibit phosphorylation of transforming growth factor ? activated kinase-1 (TAK1), MEK4, c-Jun N-terminal kinase, and IkappaB kinase as well as activation of nuclear factor kappa B through regulating ..
  7. Zografos E, Anagnostopoulos A, Papadopoulou A, Legaki E, Zagouri F, Marinos E, et al. Serum Proteomic Signatures of Male Breast Cancer. Cancer Genomics Proteomics. 2019;16:129-137 pubmed publisher
    ..These findings provide valuable insight into the distinct clinicopathological features of MBC and indicate that select serum proteomic markers may help improve MBC management. ..
  8. Kim H, Kim M, Cho J. Alisma canaliculatum ethanol extract suppresses inflammatory responses in LPS-stimulated macrophages, HCl/EtOH-induced gastritis, and DSS-triggered colitis by targeting Src/Syk and TAK1 activities. J Ethnopharmacol. 2018;219:202-212 pubmed publisher
    ..that Src and Syk, as well as molecular association between TAK1 and mitogen-activated protein kinase kinase 4/7 (MKK4/7), were targeted by Ac-EE...
  9. Sarikhani M, Mishra S, Desingu P, Kotyada C, Wolfgeher D, Gupta M, et al. SIRT2 regulates oxidative stress-induced cell death through deacetylation of c-Jun NH2-terminal kinase. Cell Death Differ. 2018;25:1638-1656 pubmed publisher
    ..Furthermore, SIRT2-mediated deacetylation favours the phosphorylation of JNK by MKK4, an upstream kinase...
  10. Zhang Q, Zhao L, Tian X, Yan C, Li Y, Liu Y, et al. The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance. Hepatology. 2017;66:834-854 pubmed publisher
    ..with apoptosis signal-regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7-JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance, and hepatic steatosis...
  11. Poudel A, Zhou J, Mekala N, Welchko R, Rosca M, Li L. Berberine protects against cytokine-induced inflammation through multiple pathways in undifferentiated C2C12 myoblast cells. Can J Physiol Pharmacol. 2019;: pubmed publisher
    ..including activation of the AMPKα-SIRT-1-PGC-1 α, inhibition of the Mitogen-activated protein kinase kinase 4 (MKK4)-SAP/JUNK-C-JUN as well as protection of mitochondrial bioenergetics ...
  12. Shortall S, Negm O, Fowler M, Fairclough L, Tighe P, Wigmore P, et al. Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885. Mol Neurobiol. 2018;55:7413-7430 pubmed publisher
    ..expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3)...
  13. Yoo S, Kim M, Cho J. Syk and Src-targeted anti-inflammatory activity of aripiprazole, an atypical antipsychotic. Biochem Pharmacol. 2018;148:1-12 pubmed publisher
    ..Similar to these data, c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 4 (MKK4), MKK7, and transforming growth factor beta-activated kinase 1 (TAK1) for AP-1 activation, and inhibitor of κBα (..
  14. Zaha V, Qi D, Su K, Palmeri M, Lee H, Hu X, et al. AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. J Mol Cell Cardiol. 2016;91:104-13 pubmed publisher
    ..KD hearts showed increased activation of the mitogen activated protein kinase kinase 4 (MKK4) and downstream c-Jun terminal kinase (JNK) and greater necrosis during reperfusion after coronary occlusion...
  15. Sommerfeld A, Reinehr R, Haussinger D. Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms. Cell Physiol Biochem. 2015;36:866-83 pubmed publisher
    ..phosphatase 1 (MKP-1), which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4) and c-jun-NH2-terminal kinase (JNK) activation...
  16. Wu W, Huang Q, He F, Xiao M, Pang S, Guo X, et al. Roles of mitogen-activated protein kinases in the modulation of endothelial cell function following thermal injury. Shock. 2011;35:618-25 pubmed publisher
    ..using the dominant negative adenoviral approach of MAPK kinase 3b and MAPK kinase 6b to block p38 MAPKs, and MKK4 and MKK7 to block JNK MAPKs, show that the latter MAPKs are involved in the regulation of P selectin and ..
  17. Iqbal S, Howard S, LoGrasso P. Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway. Mol Cell Biol. 2015;35:1992-2006 pubmed publisher
    ..dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3β (GSK3β) and thereby decreasing ER and oxidative stress...
  18. Divya S, Wang X, Pratheeshkumar P, Son Y, Roy R, Kim D, et al. Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin. Toxicol Appl Pharmacol. 2015;284:92-99 pubmed publisher BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), ..
  19. Feng R, Wang Y, Liu C, Yan C, Zhang H, Su H, et al. Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice endogenously synthesizing long-chain n-3 fatty acids. Biochem Pharmacol. 2018;154:75-88 pubmed publisher
    ..activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1)/mitogen-activated protein kinase kinase 4 (MKK4) pathway...
  20. Huwait E, Greenow K, Singh N, Ramji D. A novel role for c-Jun N-terminal kinase and phosphoinositide 3-kinase in the liver X receptor-mediated induction of macrophage gene expression. Cell Signal. 2011;23:542-9 pubmed publisher
    ..LXR agonists activated several components of the JNK pathway (SEK1, JNK and c-Jun) along with AKT, a downstream target for PI3K...
  21. Goldberg A, Cho E, Miller C, Lou H, Turk B. Identification of a Substrate-selective Exosite within the Metalloproteinase Anthrax Lethal Factor. J Biol Chem. 2017;292:814-825 pubmed publisher
    ..One residue in particular, Trp-271, is essential for cleavage of MKK3, MKK4, and MKK6 but dispensable for targeting of MEK1, MEK2, and NLRP1B...
  22. Neganova I, Shmeleva E, Munkley J, Chichagova V, Anyfantis G, Anderson R, et al. JNK/SAPK Signaling Is Essential for Efficient Reprogramming of Human Fibroblasts to Induced Pluripotent Stem Cells. Stem Cells. 2016;34:1198-212 pubmed publisher
    ..Using both chemical inhibitors and RNA interference of MKK4, MKK7 and JNK1, we tested the role of JNK/SAPK signaling during the initiation stage of neonatal and adult ..
  23. Vaden J, Bhattacharyya B, Chen P, Watson J, Marshall A, Phillips S, et al. Ubiquitin-specific protease 14 regulates c-Jun N-terminal kinase signaling at the neuromuscular junction. Mol Neurodegener. 2015;10:3 pubmed publisher activation of MLK3 by ubiquitination, we also observed increased activation of its downstrea targets MAP kinase kinase 4 (MKK4) and c-Jun N-terminal kinase (JNK)...
  24. Kramer P, Duan J, Gaffrey M, Shukla A, Wang L, Bammler T, et al. Fatiguing contractions increase protein S-glutathionylation occupancy in mouse skeletal muscle. Redox Biol. 2018;17:367-376 pubmed publisher
    ..This study lays the groundwork for future investigation into the altered exercise adaptation associated with chronic conditions, such as sarcopenia. ..
  25. Ti Y, Xie G, Wang Z, Ding W, Zhang Y, Zhong M, et al. Tribbles 3: A potential player in diabetic aortic remodelling. Diab Vasc Dis Res. 2016;13:69-80 pubmed publisher
    ..with Tribbles 3 silencing, the diminished phosphorylation of PI3K/Akt was restored, and increased activation of MKK4/JNK was decreased...
  26. Shen K, Xie J, Wang H, Zhang H, Yu M, Lu F, et al. Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells. Mol Cancer Ther. 2015;14:1738-49 pubmed publisher
    ..Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway...
  27. Frigolet M, Thomas G, Beard K, Lu H, Liu L, Fantus I. The bradykinin-cGMP-PKG pathway augments insulin sensitivity via upregulation of MAPK phosphatase-5 and inhibition of JNK. Am J Physiol Endocrinol Metab. 2017;313:E321-E334 pubmed publisher
    ..Whereas insulin-stimulated phosphorylation of upstream activators of JNK and ERK, i.e., MKK4 and MEK1/2, was unaffected, BK augmented insulin-mediated induction of MKP-5 mRNA and protein levels...
  28. Houtman M, Shchetynsky K, Chemin K, Hensvold A, Ramsköld D, Tandre K, et al. T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. J Autoimmun. 2018;90:28-38 pubmed publisher
    ..Overall, our data suggests the involvement of LINC01882 in T cell activation and hints towards an auxiliary role of these non-coding SNPs in autoimmunity associated with the PTPN2 locus. ..
  29. Ishikawa T, Shimada S, Fukai M, Kimura T, Umemoto K, Shibata K, et al. Post-reperfusion hydrogen gas treatment ameliorates ischemia reperfusion injury in rat livers from donors after cardiac death: a preliminary study. Surg Today. 2018;48:1081-1088 pubmed publisher
    ..The phosphorylation of cytoplasmic MKK4 and JNK were enhanced in the NT group and suppressed in the H2 group...
  30. Hoang B, Shi Y, FROST P, Mysore V, Bardeleben C, Lichtenstein A. SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism. Mol Cancer Res. 2016;14:397-407 pubmed publisher
    ..Enhanced SGK expression and activity in multiple myeloma cells contributes to resistance to ER stress, including bortezomib challenge. ..
  31. Yan H, Zhao Y, Shi H, Li J, Wang Y, Tang D. BRASSINOSTEROID-SIGNALING KINASE1 Phosphorylates MAPKKK5 to Regulate Immunity in Arabidopsis. Plant Physiol. 2018;176:2991-3002 pubmed publisher
    ..Furthermore, MAPKKK5 interacts with multiple MAPK kinases, including MKK1, MKK2, MKK4, MKK5, and MKK6...
  32. Zhou J, Xu G, Bai Z, Li K, Yan J, Li F, et al. Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway. Toxicol Appl Pharmacol. 2015;289:409-18 pubmed publisher
    ..contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling...
  33. Li K, Yang F, Zhang G, Song S, Li Y, Ren D, et al. AIK1, A Mitogen-Activated Protein Kinase, Modulates Abscisic Acid Responses through the MKK5-MPK6 Kinase Cascade. Plant Physiol. 2017;173:1391-1408 pubmed publisher
    ..The single mutant seedlings of mpk6 and mkk5 have similar phenotypes to aik1, but mkk4 does not...
  34. Hirai S, Katoh M, Terada M, Kyriakis J, Zon L, Rana A, et al. MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem. 1997;272:15167-73 pubmed
    ..The activity of SEK1/MKK4/JNKK, a MAPK kinase class protein kinase designated as a direct activator of JNK/SAPK, is also induced by MUK/DLK/..
  35. Xia Y, Wu Z, Su B, Murray B, Karin M. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. 1998;12:3369-81 pubmed
    ..The specificity of JNK activation is determined by the MAPKK JNKK1, which interacts with the MAPKKK MEKK1 and JNK through its amino-terminal extension...
  36. Lee H, Srinivas H, Xia D, Lu Y, Superty R, Lapushin R, et al. Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival. J Biol Chem. 2003;278:23630-8 pubmed
    ..Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts...
  37. Shao N, Wang Y, Lu K, Jiang W, Li Q, Wang N, et al. Role of the functional MKK4 promoter variant (-1304T>G) in a decreased risk of prostate cancer: case-control study and meta-analysis. J Cancer Res Clin Oncol. 2012;138:1531-9 pubmed publisher
    b>MKK4 has been suggested as a tumor suppressor. The functional variant (-1304T>G) in the MKK4 promoter has been implicated as a risk factor for many types of cancer. However, its role in prostate cancer (PCa) is unclear...
  38. Alexeyenko A, Alkasalias T, Pavlova T, Szekely L, Kashuba V, Rundqvist H, et al. Confrontation of fibroblasts with cancer cells in vitro: gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth. J Exp Clin Cancer Res. 2015;34:62 pubmed publisher
    ..We also demonstrated functional congruence between the in vitro and ex vivo models. The microarray data are made available via the Gene Expression Omnibus as GSE57199. ..
  39. Banerjee S, McGee D. ROCK activity affects IL-1-induced signaling possibly through MKK4 and p38 MAPK in Caco-2 cells. In Vitro Cell Dev Biol Anim. 2016;52:878-84 pubmed publisher
    ..Here, we extend these studies by showing that inhibiting ROCK suppressed the IL-1-induced phosphorylation of MKK4, a known activator of JNK, but not MKK7...
  40. Dunnill C, Ibraheem K, Mohamed A, Southgate J, Georgopoulos N. A redox state-dictated signalling pathway deciphers the malignant cell specificity of CD40-mediated apoptosis. Oncogene. 2017;36:2515-2528 pubmed publisher
    ..cascade underpinning mCD40L-mediated death as involving sequential TRAF3 stabilisation, ASK1 phosphorylation, MKK4 (but not MKK7) activation and JNK/AP-1 induction, leading to a Bak- and Bax-dependent mitochondrial apoptosis ..
  41. Fung T, Liu D. Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun. Cell Death Dis. 2017;8:3215 pubmed publisher
    ..Of the two known upstream MAPK kinases (MKK), MKK7, but not MKK4, was shown to be responsible for IBV-induced JNK activation...
  42. Merritt S, Mata M, Nihalani D, Zhu C, Hu X, Holzman L. The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. J Biol Chem. 1999;274:10195-202 pubmed
    ..Unlike MLK3, however, DLK did not phosphorylate or activate recombinant MKK4 in vitro. In confirmatory experiments performed in vivo, DLK both associated with and activated MKK7...
  43. Ho D, Bardwell A, Grewal S, Iverson C, Bardwell L. Interacting JNK-docking sites in MKK7 promote binding and activation of JNK mitogen-activated protein kinases. J Biol Chem. 2006;281:13169-79 pubmed
    ..D-site has been identified near the N terminus of each of the MAPK kinases (MKKs or MEKs) MEK1, MEK2, MKK3, MKK4, and MKK6...
  44. Matsumoto T, Kinoshita T, Kirii Y, Yokota K, Hamada K, Tada T. Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state. Biochem Biophys Res Commun. 2010;400:369-73 pubmed publisher
    b>MKK4 activates both JNKs and p38s. We determined the crystal structures of human non-phosphorylated MKK4 kinase domain (npMKK4) complexed with AMP-PNP (npMKK4/AMP) and a ternary complex of npMKK4, AMP-PNP and p38? peptide (npMKK4/AMP/p38)...
  45. Zhu Y, Wang C, Yu M, Cui J, Liu L, Xu Z. ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein Cell. 2013;4:711-21 pubmed publisher
    ..In addition to ULK1, we found that LRRK2 interacts with the endogenous MKK4/7, JIP3 and coordinates with them in the activation of JNK signaling...
  46. Zhang H, Lin X, Han Z, Wang J, Qu L, Chai J. SERK Family Receptor-like Kinases Function as Co-receptors with PXY for Plant Vascular Development. Mol Plant. 2016;9:1406-1414 pubmed publisher
    ..TDIF induces interaction of its receptor PXY with SERKs in vitro and in vivo. Furthermore, the serk1-1 serk2-1 bak1-5 mutant plants are less sensitive to TDIF, phenocopying the pxy mutant with a compromised ..
  47. Iqbal B, Masood A, Lone M, Lone A, Dar N. Polymorphism of Metastasis Suppressor Genes MKK4 and NME1 in Kashmiri Patients with Breast Cancer. Breast J. 2016;22:673-677 pubmed publisher
    Genetic polymorphisms in metastatic suppressor genes like MKK4 and NME1 are not well studied in breast cancer. Hence, we analyzed the relationship between MKK4 and NME1 polymorphisms and breast cancer risk in Kashmir, India...
  48. 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)...
  49. Yuan Q, Song C, Gao L, Zhang H, Yang C, Sheng J, et al. Transcriptome de novo assembly and analysis of differentially expressed genes related to cytoplasmic male sterility in onion. Plant Physiol Biochem. 2018;125:35-44 pubmed publisher
    ..expressed genes, we identified two cytoplasmic control genes, atp9 and cox1, and three nuclear-related genes, SERK1, AG and AMS. These transcriptomic results were also verified by fluorescence quantitative PCR...
  50. 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...
  51. Li X, MacLeod R, Dunlop A, Edwards H, Advant N, Gibson L, et al. A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex. FEBS Lett. 2009;583:3310-6 pubmed publisher
    ..N-domain and C-terminus of beta arrestin 1 and beta arrestin 2 we identify two novel apoptosis signal-regulating kinase 1 binding sites and in the N-domain of the beta arrestin 1 and beta arrestin 2 we identify a novel MKK4 docking site.
  52. Li Y, Zhao Y, Jiang R, Xu Y, Ling M, Pang Y, et al. DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis in human embryo lung fibroblast cells. Toxicol Lett. 2012;210:302-10 pubmed publisher
    ..These results suggest that DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis. ..
  53. Horvatova A, Utaipan T, Otto A, Zhang Y, Gan Schreier H, Pavek P, et al. Ursodeoxycholyl lysophosphatidylethanolamide negatively regulates TLR-mediated lipopolysaccharide response in human THP-1-derived macrophages. Eur J Pharmacol. 2018;825:63-74 pubmed publisher
    ..indirect immunofluorescence analyses revealed that UDCA-18:1LPE attenuated the expression of phosphorylated p38, MKK4/MKK7, JNK1/2, and c-Jun as well as nuclear translocation of NF-?B by ~ 22-86%...
  54. 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
    ..within protein kinase subdomain X in the MAP3K, MEKK1, that are critical for its interaction with the MAP2K, MKK4, and MEKK1-induced MKK4 activation...
  55. Chen Z, Cobb M. Activation of MEKK1 by Rho GTPases. Methods Enzymol. 2006;406:468-78 pubmed
    ..We also briefly explain the methods and conditions we use to identify the interaction between MEKK1 and RhoA in yeast and in mammalian cells. ..
  56. Abba M, Gong T, Lu Y, Lee J, Zhong Y, Lacunza E, et al. A Molecular Portrait of High-Grade Ductal Carcinoma In Situ. Cancer Res. 2015;75:3980-90 pubmed publisher
    ..We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. ..
  57. Jiang B, Zhang J, Xia J, Zhao W, Wu Y, Shi M, et al. IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation. Cell Rep. 2017;19:389-400 pubmed publisher
    ..Upon SS, Cdc42 normally disrupts mixed lineage kinase 3's (MLK3's) auto-inhibition, triggering the MLK3-MKK4/7-JNK-Bim apoptotic cascade...
  58. Enomoto A, Kido N, Ito M, Morita A, Matsumoto Y, Takamatsu N, et al. Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). Oncogene. 2008;27:1930-8 pubmed
    ..STK38 inhibited MEKK1/2 activation without preventing MEKK1/2 binding to its substrate, SEK1. Importantly, STK38 suppressed the autophosphorylation of MEKK2 without interfering with MEKK2 dimer formation, and ..
  59. Deng G, Zheng X, Jiang P, Chen K, Wang X, Jiang K, et al. Notch1 suppresses prostate cancer cell invasion via the metastasis-associated 1-KiSS-1 metastasis-suppressor pathway. Oncol Lett. 2017;14:4477-4482 pubmed publisher
    ..1 (MTA1) and increase of KiSS-1 metastasis-suppressor (KISS-1), mitogen-activated protein kinase 4 (MKK4) and cluster of differentiation 82 (KAI1)...
  60. Song J, Lee Y. Daxx deletion mutant (amino acids 501-625)-induced apoptosis occurs through the JNK/p38-Bax-dependent mitochondrial pathway. J Cell Biochem. 2004;92:1257-70 pubmed
    ..In contrast, phosphorylation of Bim is upstream of caspase-9 activation. Taken together, our results suggest that Daxx501-625-induced apoptosis is mediated through the ASK1-MEK-JNK/p38-Bim-Bax-dependent caspase pathway. ..
  61. Xin W, Yun K, Ricci F, Zahurak M, Qiu W, Su G, et al. MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course. Clin Cancer Res. 2004;10:8516-20 pubmed
    MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase...
  62. Liu J, Xu D, Wang Q, Zheng D, Jiang X, Xu L. LPS induced miR-181a promotes pancreatic cancer cell migration via targeting PTEN and MAP2K4. Dig Dis Sci. 2014;59:1452-60 pubmed publisher
    ..These results suggest that the LPS-TLR4-miR-181a signaling pathway plays a significant role in pancreatic cancer invasion and progression. ..
  63. Mundt F, Rajput S, Li S, Ruggles K, Mooradian A, Mertins P, et al. Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers. Cancer Res. 2018;78:2732-2746 pubmed publisher
    ..b>Significance: Integrative phosphoproteogenomic analysis is used to determine intrinsic resistance mechanisms of triple-negative breast tumors to PI3K inhibition. Cancer Res; 78(10); 2732-46. ©2018 AACR. ..
  64. Inoshita S, Takeda K, Hatai T, Terada Y, Sano M, Hata J, et al. Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress. J Biol Chem. 2002;277:43730-4 pubmed
    ..JNK-dependent phosphorylation and thus inactivation of Mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. ..
  65. Zhang P, Liu S, Ngan H. TAp73-mediated the activation of c-Jun N-terminal kinase enhances cellular chemosensitivity to cisplatin in ovarian cancer cells. PLoS ONE. 2012;7:e42985 pubmed publisher
    ..protein GADD45 alpha (GADD45α) and subsequently activating mitogen-activated protein kinase kinase-4 (MKK4)...
  66. Kaltenmeier C, Vollmer L, Vernetti L, Caprio L, Davis K, Korotchenko V, et al. A Tumor Cell-Selective Inhibitor of Mitogen-Activated Protein Kinase Phosphatases Sensitizes Breast Cancer Cells to Lymphokine-Activated Killer Cell Activity. J Pharmacol Exp Ther. 2017;361:39-50 pubmed publisher
    ..BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses...
  67. Li W, Zhu J, Dou J, She H, Tao K, Xu H, et al. Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy. Nat Commun. 2017;8:1763 pubmed publisher
    ..ER stressors lead to a PERK-dependent activation and recruitment of MKK4 to lysosomes, activating p38 MAPK at lysosomes...
  68. Das K, Muniyappa H. c-Jun-NH2 terminal kinase (JNK)-mediates AP-1 activation by thioredoxin: phosphorylation of cJun, JunB, and Fra-1. Mol Cell Biochem. 2010;337:53-63 pubmed publisher
    ..Further, increased expression of Trx induced the phosphorylation of MKK4 and MKK7 which are upstream kinases of the JNK signaling cascade...
  69. Clavier A, Rincheval Arnold A, Baillet A, Mignotte B, Guénal I. Two different specific JNK activators are required to trigger apoptosis or compensatory proliferation in response to Rbf1 in Drosophila. Cell Cycle. 2016;15:283-94 pubmed publisher
    ..The core of this signaling pathway, composed of a JNK protein and a JNK kinase (JNKK), can be activated by various putative JNKK kinases (JNKKK) which are themselves downstream of different adaptor ..
  70. Ahn J, Ann E, Kim M, Yoon J, Lee H, Jo E, et al. Autophagy negatively regulates tumor cell proliferation through phosphorylation dependent degradation of the Notch1 intracellular domain. Oncotarget. 2016;7:79047-79063 pubmed publisher
    ..These results show that autophagy inhibits Notch1 signaling by promoting Notch1-IC degradation and therefore plays a role in tumor suppression. ..
  71. 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...
  72. 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. ..
  73. Hernández E, Lee S, Kim J, Duran A, Linares J, Yajima T, et al. A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. Cell Metab. 2014;20:499-511 pubmed publisher
    ..Together, these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose tissue inflammation in obesity. ..
  74. Bequette C, Hind S, Pulliam S, Higgins R, Stratmann J. MAP kinases associate with high molecular weight multiprotein complexes. J Exp Bot. 2017;: pubmed publisher
    ..we report that MPK3, MPK6, and MPK10 orthologs in tomato, tobacco, and Arabidopsis as well as tomato MAPK kinase 4 (MKK4) associate with high molecular weight (~250-550 kDa) multiprotein complexes...
  75. 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...
  76. Huber T, Kottgen M, Schilling B, Walz G, Benzing T. Interaction with podocin facilitates nephrin signaling. J Biol Chem. 2001;276:41543-6 pubmed
    ..Mutational analysis suggests that abnormal or inefficient signaling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria. ..
  77. Su G, Song J, Repasky E, Schutte M, Kern S. Mutation rate of MAP2K4/MKK4 in breast carcinoma. Hum Mutat. 2002;19:81 pubmed
    ..The mitogen-activated protein kinase kinase (MAPKK) homolog MAP2K4 (MKK4, SEK, JNKK1) is a centrally-placed mediator of the SAPK pathways...
  78. Zhou G, Golden T, Aragon I, Honkanen R. Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. J Biol Chem. 2004;279:46595-605 pubmed
    ..domain of ASK-1, and studies with siRNA targeting PP5 indicate that PP5 acts to suppress the phosphorylation of MKK4 (Thr-261), JNK (Thr-183/Tyr-185), and c-Jun (Ser-63) without affecting the activating phosphorylation of p38 MAPK (..
  79. Kim S, Moon C, Eun S, Ryu P, Jo S. Identification of ASK1, MKK4, JNK, c-Jun, and caspase-3 as a signaling cascade involved in cadmium-induced neuronal cell apoptosis. Biochem Biophys Res Commun. 2005;328:326-34 pubmed
    ..Taken together, our data suggested that the JNK/c-Jun signaling cascade plays a crucial role in Cd-induced neuronal cell apoptosis and provides a molecular linkage between oxidative stress and neuronal apoptosis. ..
  80. Robinson V, Shalhav O, Otto K, Kawai T, Gorospe M, Rinker Schaeffer C. Mitogen-activated protein kinase kinase 4/c-Jun NH2-terminal kinase kinase 1 protein expression is subject to translational regulation in prostate cancer cell lines. Mol Cancer Res. 2008;6:501-8 pubmed publisher
    Mitogen-activated protein kinase kinase 4/c-Jun NH(2)-terminal kinase kinase 1 (MKK4/JNKK1; hereafter referred to as MKK4) is a dual-specificity kinase with a critical role in regulating the activity of c-Jun NH(2)-terminal kinase and ..
  81. Song X, Coffa S, Fu H, Gurevich V. How does arrestin assemble MAPKs into a signaling complex?. J Biol Chem. 2009;284:685-95 pubmed publisher
    ..Here we have demonstrated that all four vertebrate arrestins interact with JNK3, MKK4, and ASK1, but only arrestin3 facilitates JNK3 activation...
  82. Otto K, Acharya S, Robinson V. Stress-activated kinase pathway alteration is a frequent event in bladder cancer. Urol Oncol. 2012;30:415-20 pubmed publisher
    ..UMUC-3, J82, 5637, 253J, and 253J-BV) were analyzed by immunoblotting for the JNK and p38 MAPKs, as well as MKK3, MKK4, MKK6, and MKK7. Quantitative real time PCR was utilized to determine mRNA expression levels of the MAP2Ks...
  83. Kyriakis J, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689-737 pubmed publisher
    ..Herein we first summarize the molecular components of the mammalian stress-regulated MAPK pathways and their regulation as described thus far. We then review some of the in vivo functions of these pathways. ..
  84. Tanaka T, Iino M, Goto K. Knockdown of Sec8 enhances the binding affinity of c-Jun N-terminal kinase (JNK)-interacting protein 4 for mitogen-activated protein kinase kinase 4 (MKK4) and suppresses the phosphorylation of MKK4, p38, and JNK, thereby inhibiting apoptosis. FEBS J. 2014;281:5237-50 pubmed publisher
    ..These results raise the possibility that Sec8 serves as an important regulator of MAPK signaling cascades. ..
  85. Geng P, Ou J, Xie G, Li J, Zhao X, Xiang L, et al. Mitogen-Activated Protein Kinase Kinase 4 Gene Polymorphism and Cancer Risk. Medicine (Baltimore). 2015;94:e0938 pubmed publisher
    A number of epidemiological studies have assessed the association of -1304T > G polymorphism in the MKK4 gene and risk of cancer, but the results lack of statistical power due to the limited subjects used in these studies...
  86. Lv H. lncRNA-Map2k4 sequesters miR-199a to promote FGF1 expression and spinal cord neuron growth. Biochem Biophys Res Commun. 2017;490:948-954 pubmed publisher
    ..Thus, lncRNA-Map2k4 regulates neuronal proliferation and apoptosis through a miR-199a/FGF1 pathway. This finding provides more evidence for the role of lncRNAs in SCI. ..
  87. Yuan G, Li H, Yang W. The integration of Gβ and MAPK signaling cascade in zygote development. Sci Rep. 2017;7:8732 pubmed publisher
    ..In this study, we demonstrate that Arabidopsis Gβ protein AGB1 interacts with MPK3 and 6, MKK4 and 5, as well as the regulatory domains of YODA (YDA), the upstream MEKK of MKK4/5...
  88. Jeon E, Song H, Kim M, Moon H, Bae Y, Jung J, et al. Sphingosylphosphorylcholine induces proliferation of human adipose tissue-derived mesenchymal stem cells via activation of JNK. J Lipid Res. 2006;47:653-64 pubmed
    ..These results indicate that SPC stimulates the proliferation of hADSCs through the Gi/Go-PLC-JNK pathway and that LPA receptors may be responsible in part for the SPC-induced proliferation. ..
  89. Gloeckner C, Schumacher A, Boldt K, Ueffing M. The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J Neurochem. 2009;109:959-68 pubmed publisher
    ..Our findings present evidence of a new class of molecular targets for mutant LRRK2 that link to neurotoxicity, cellular stress, cytoskeletal dynamics and vesicular transport. ..
  90. Marasa B, Srikantan S, Masuda K, Abdelmohsen K, Kuwano Y, Yang X, et al. Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs. Sci Signal. 2009;2:ra69 pubmed publisher
    b>MKK4 (mitogen-activated protein kinase kinase 4) is a pivotal upstream activator of c-Jun N-terminal kinase and p38. Here, we report that the abundance of MKK4 increases in senescent human diploid fibroblasts through enhanced translation...
  91. Pan W, Wang H, Jianwei R, Ye Z. MicroRNA-27a promotes proliferation, migration and invasion by targeting MAP2K4 in human osteosarcoma cells. Cell Physiol Biochem. 2014;33:402-12 pubmed publisher
    ..These findings may help us understand the molecular mechanism of miR-27a in the tumorigenesis of osteosarcoma and may provide new diagnostic and therapeutic options for the treatment of this neoplasia. ..
  92. Kundumani Sridharan V, Subramani J, Das K. Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells. J Biol Chem. 2015;290:17505-19 pubmed publisher
    The mitogen-activated protein kinase kinase 4 (MKK4) is activated via phosphorylation of Ser-257 and Thr-261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress...