Gene Symbol: MAP2K7
Description: mitogen-activated protein kinase kinase 7
Alias: JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4, dual specificity mitogen-activated protein kinase kinase 7, JNK-activating kinase 2, MAP kinase kinase 7, MAPK/ERK kinase 7, SAPK kinase 4, c-Jun N-terminal kinase kinase 2, stress-activated protein kinase kinase 4
Species: human
Products:     MAP2K7

Top Publications

  1. Kristensen O, Guenat S, Dar I, Allaman Pillet N, Abderrahmani A, Ferdaoussi M, et al. A unique set of SH3-SH3 interactions controls IB1 homodimerization. EMBO J. 2006;25:785-97 pubmed
    ..Taken together, these results indicate that IB1 homodimerization through its SH3 domain has pleiotropic effects including regulation of the insulin secretion process. ..
  2. Tornatore L, Marasco D, Dathan N, Vitale R, Benedetti E, Papa S, et al. Gadd45 beta forms a homodimeric complex that binds tightly to MKK7. J Mol Biol. 2008;378:97-111 pubmed publisher
    ..In fibroblasts this mechanism involves the inactivation of MKK7, the upstream activator of JNK, by direct binding within the kinase ATP pocket...
  3. Tournier C, Whitmarsh A, Cavanagh J, Barrett T, Davis R. Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Proc Natl Acad Sci U S A. 1997;94:7337-42 pubmed
    ..Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK...
  4. Yasuda J, Whitmarsh A, Cavanagh J, Sharma M, Davis R. The JIP group of mitogen-activated protein kinase scaffold proteins. Mol Cell Biol. 1999;19:7245-54 pubmed
    ..JIP) group of scaffold proteins selectively mediates signaling by the mixed-lineage kinase (MLK)-->MAP kinase kinase 7 (MKK7)-->JNK pathway...
  5. Kelkar N, Gupta S, Dickens M, Davis R. Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Mol Cell Biol. 2000;20:1030-43 pubmed
    ..JIP3 is a member of a novel class of putative MAPK scaffold proteins that may regulate signal transduction by the JNK pathway. ..
  6. Tournier C, Dong C, Turner T, Jones S, Flavell R, Davis R. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 2001;15:1419-26 pubmed
    ..Two MAPK kinases (MKK4 and MKK7) can activate the c-Jun NH(2)-terminal kinase (JNK) group of MAPK in vitro...
  7. Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M. A novel dual specificity phosphatase SKRP1 interacts with the MAPK kinase MKK7 and inactivates the JNK MAPK pathway. Implication for the precise regulation of the particular MAPK pathway. J Biol Chem. 2002;277:23909-18 pubmed
    ..However, SKRP1 does not bind directly to its target JNK, but co-precipitation of SKRP1 with the MAPK kinase MKK7, a JNK activator, was found in vitro and in vivo...
  8. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, et al. Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol. 2004;6:146-53 pubmed
    ..However, the mechanisms by which Gadd45 beta inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2--a specific and essential activator of JNK--as a target of Gadd45 beta, and in fact, of NF-kappa B itself...
  9. Takekawa M, Tatebayashi K, Saito H. Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol Cell. 2005;18:295-306 pubmed
    ..Synthetic DVD oligopeptides inhibited specific MAPKK activation, both in vitro and in vivo, demonstrating the critical importance of the DVD docking in MAPK signaling. ..

More Information

Publications175 found, 100 shown here

  1. Varin A, Decrion A, Sabbah E, Quivy V, Sire J, Van Lint C, et al. Synthetic Vpr protein activates activator protein-1, c-Jun N-terminal kinase, and NF-kappaB and stimulates HIV-1 transcription in promonocytic cells and primary macrophages. J Biol Chem. 2005;280:42557-67 pubmed
    ..Synthetic HIV-1 Vpr protein activated AP-1, c-Jun N-terminal kinase, and MKK7 in both U937 cells and primary macrophages...
  2. 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
    ..Here we demonstrated that MKK7 recognizes its target JNK by a novel mechanism involving a partially cooperative interaction of three low affinity ..
  3. Papa S, Monti S, Vitale R, Bubici C, Jayawardena S, Alvarez K, et al. Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. J Biol Chem. 2007;282:19029-41 pubmed
    ..Inhibition of TNFalpha-induced JNK signaling by Gadd45beta depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45beta blunts MKK7, however, is unknown...
  4. Blanco S, Santos C, Lazo P. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol Cell Biol. 2007;27:7273-83 pubmed
    ..Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response. ..
  5. Wasserman T, Katsenelson K, Daniliuc S, Hasin T, Choder M, Aronheim A. A novel c-Jun N-terminal kinase (JNK)-binding protein WDR62 is recruited to stress granules and mediates a nonclassical JNK activation. Mol Biol Cell. 2010;21:117-30 pubmed publisher
    ..JNK inhibition results in reduced number and size of SG and reduced size of PB. Collectively, we propose that JNK and WDR62 may regulate the dynamic interplay between polysomes SG and PB, thereby mediating mRNA fate after stress. ..
  6. Prinz E, Aviram S, Aronheim A. WDR62 mediates TNFα-dependent JNK activation via TRAF2-MLK3 axis. Mol Biol Cell. 2018;29:2470-2480 pubmed publisher
    ..WD repeat domain 62 (WDR62) is a JNK scaffold protein, interacting with JNK, MKK7, and several MAP3Ks. The loss of WDR62 in human leads to microcephaly and pachygyria...
  7. Zhang B, Liang A, Fu Y. Ac34 protein of AcMNPV promoted progeny virus production and induced the apoptosis in host Sf9 cells. Biotechnol Lett. 2019;41:147-158 pubmed publisher
    ..c-Jun N-terminal kinase (JNK) activation requires MKK4 and MKK7 mediated phosphorylation at Thr183 and Tyr185...
  8. Cheng J, Yang J, Xia Y, Karin M, Su B. Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation. Mol Cell Biol. 2000;20:2334-42 pubmed
    ..MAPKKK MEKK2, we found that strong and specific JNK1 activation by MEKK2 was mediated by the MAPKK JNK kinase 2 (JNKK2) rather than by JNKK1 through formation of a tripartite complex consisting of MEKK2, JNKK2, and JNK1...
  9. Repici M, Centeno C, Tomasi S, Forloni G, Bonny C, Vercelli A, et al. Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation. Neuroscience. 2007;150:40-9 pubmed
    ..We also examined the activation of the two direct JNK activators, MAP kinase kinase 4 (MKK4) and MAP kinase kinase 7 (MKK7). MKK4 showed the same time course as JNK in both core and penumbra, reaching peak activation at 6 h...
  10. Hui B, Zhang L, Zhou Q, Hui L. Pristimerin Inhibits LPS-Triggered Neurotoxicity in BV-2 Microglia Cells Through Modulating IRAK1/TRAF6/TAK1-Mediated NF-κB and AP-1 Signaling Pathways In Vitro. Neurotox Res. 2018;33:268-283 pubmed publisher
    ..limiting TGF-beta activating kinase 1 (TAK1) activation, and resulting in an inhibition of IKKα/β/NF-κB and MKK7/JNK/AP-1 signaling pathway in LPS-activated BV-2 microglia...
  11. Qu F, Tang J, Peng X, Zhang H, Shi L, Huang Z, et al. Two novel MKKs (MKK4 and MKK7) from Ctenopharyngodon idella are involved in the intestinal immune response to bacterial muramyl dipeptide challenge. Dev Comp Immunol. 2019;93:103-114 pubmed publisher
    ..idella, which may provide new insight into the bacterial-induced intestinal inflammation of bony fishes. ..
  12. 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
    ..Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking ..
  13. Repici M, Mare L, Colombo A, Ploia C, Sclip A, Bonny C, et al. c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4 and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and extracellular signal-regulated ki. Neuroscience. 2009;159:94-103 pubmed publisher
    ..upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain...
  14. Shi W, Wang Y, Peng J, Qi S, Vitale N, Kaneda N, et al. EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells. J Biol Chem. 2019;294:6871-6887 pubmed publisher
    ..pathway from EPHB6 to tyrosine hydroxylase expression in AGCCs involves Rac family small GTPase 1 (RAC1), MAP kinase kinase 7 (MKK7), c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, activator protein 1 (AP1), and early growth ..
  15. Yamasaki T, Deki Arima N, Kaneko A, Miyamura N, Iwatsuki M, Matsuoka M, et al. Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7. Sci Rep. 2017;7:7348 pubmed publisher
    ..A specific upstream activator of JNKs is the mitogen-activated protein kinase kinase 7 (MKK7)...
  16. Perry N, Kaoud T, Ortega O, Kaya A, Marcus D, Pleinis J, et al. Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification. Proc Natl Acad Sci U S A. 2019;116:810-815 pubmed publisher
    ..experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without ..
  17. Sun Y, Li T, Song L, Zhang C, Li J, Lin Z, et al. Liver-specific deficiency of unc-51 like kinase 1 and 2 protects mice from acetaminophen-induced liver injury. Hepatology. 2018;67:2397-2413 pubmed publisher
    ..Ulk1-dependent phosphorylation of MKK7 was further confirmed by a context-dependent phosphorylation antibody...
  18. Itoh A, Wang Z, Ito Y, Reddy U, Itoh T. SP3 acts as a positive regulator on the core promoter of human ZPK gene. Biochem Biophys Res Commun. 2004;313:612-8 pubmed
    ..Our results suggest that, for the selective expression of ZPK gene, cell-specific negative regulatory element(s) which locate outside of the core promoter region repress the potent basic promoter activity. ..
  19. 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
    ..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 intercellular ..
  20. Lu J, Zhou L, Yang G, Liang Z, Zhou W, You L, et al. Clinicopathological and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma. Hum Pathol. 2019;86:143-154 pubmed publisher
    Mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7) were shown to regulate biological behavior in many malignancies...
  21. Ung P, DeVita R, Schlessinger A. Encounter and React: Computer-Guided Design of Covalent Inhibitors. Cell Chem Biol. 2019;26:6-8 pubmed publisher
    ..2019) take a comprehensive computational and experimental approach to modulate the JNK-Jun pathway through design of MKK7 covalent inhibitors. This study highlights a promising and emerging strategy for therapeutic discovery.
  22. Tanaka S, Nakamura K, Takahasi N, Suda T. Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev. 2005;208:30-49 pubmed
    ..Herein, we review the recent advances in the research on osteoclast biology and discuss the advantages and disadvantages of anti-RANKL therapies. ..
  23. Shraga A, Olshvang E, Davidzohn N, Khoshkenar P, Germain N, Shurrush K, et al. Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor. Cell Chem Biol. 2019;26:98-108.e5 pubmed publisher
    ..selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7--one of two direct MAP2Ks that activate JNK...
  24. Syc Mazurek S, Rausch R, Fernandes K, Wilson M, Libby R. Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. Cell Death Dis. 2018;9:1095 pubmed publisher
    ..important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after ..
  25. Ueda T, Kohama Y, Kuge A, Kido E, Sakurai H. GADD45 family proteins suppress JNK signaling by targeting MKK7. Arch Biochem Biophys. 2017;635:1-7 pubmed publisher
    ..GADD45 proteins bind the JNK kinase mitogen-activated protein kinase kinase 7 (MKK7) and inhibit its activity, even under normal physiological conditions...
  26. Ramos Lopez O, Riezu Boj J, Milagro F, Martinez J. DNA methylation signatures at endoplasmic reticulum stress genes are associated with adiposity and insulin resistance. Mol Genet Metab. 2018;123:50-58 pubmed publisher
    ..0001). These included cg08188400 (MAP2K7), cg20541779 (CASP12), cg24776411 (EIF2AK1), cg14190817 (HSPA5), cg21376454 (ERN1), cg06666486 (EIF2AK1), ..
  27. Wang S, Zhang T, Yang Z, Lin J, Cai B, Ke Q, et al. Heme oxygenase-1 protects spinal cord neurons from hydrogen peroxide-induced apoptosis via suppression of Cdc42/MLK3/MKK7/JNK3 signaling. Apoptosis. 2017;22:449-462 pubmed publisher
    ..In current study we examined the role of heme oxygenase-1 (HO-1) in the modulation of MLK3/MKK7/JNK3 signaling, which is a pro-apoptotic pathway, after treating primary spinal cord neurons with H2O<..
  28. Kwon E, Choi M. Luteolin Targets the Toll-Like Receptor Signaling Pathway in Prevention of Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice. Nutrients. 2018;10: pubmed publisher
    ..A positive relationship was detected between gene expressions of Tlr5, Map2k7, Mapk12, Mapk13, and Mapk9 and lipogenesis in epididymal white adipose tissue (eWAT) of ..
  29. Mori S, Satoh T, Koide H, Nakafuku M, Villafranca E, Kaziro Y. Inhibition of Ras/Raf interaction by anti-oncogenic mutants of neurofibromin, the neurofibromatosis type 1 (NF1) gene product, in cell-free systems. J Biol Chem. 1995;270:28834-8 pubmed
    ..These results suggest that the mutant NF1-GRDs tightly bind to an oncogenic Ras in its GTP-bound active conformation and block the interaction between Ras and its effector, Raf. ..
  30. Deacon K, Blank J. MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. J Biol Chem. 1999;274:16604-10 pubmed
    ..We have examined the regulation by MEKK3 of MAPK kinase 7 (MKK7) and MKK6, two novel MAPK kinases specific for JNK and p38, respectively...
  31. Jaffe A, Hall A, Schmidt A. Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho. Curr Biol. 2005;15:405-12 pubmed
    ..with Net1 or p115RhoGEF, two Rho-specific guanine nucleotide exchange factors (GEFs), as well with MLK2 and MKK7, two of the kinase components in the JNK MAP kinase cascade...
  32. Hudson A, Stephenson N, Li C, Trotter E, Fletcher A, Katona G, et al. Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases. Sci Signal. 2018;11: pubmed publisher
    ..A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric ..
  33. Xu Q, Song B, Liu D, Chen Y, Zhou Y, Liu W, et al. The MKK7 inhibitor peptide GADD45β-I attenuates ER stress-induced mitochondrial dysfunction in HT22 cells: Involvement of JNK-Wnt pathway. Brain Res. 2018;1691:1-8 pubmed publisher
    ..JNK can be regulated by two direct upstream kinases: MAPK kinase 4 (MKK4) and MAPK kinase 7 (MKK7)...
  34. 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
    ..It is nearly identical to a recently reported human JNKK2 at the kinase domain but with major differences in both amino- and carboxyl-terminal sequences, suggesting that ..
  35. Shen Y, Park C, Suppipat K, Mistretta T, Puppi M, Horton T, et al. Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway. Leukemia. 2017;31:1314-1324 pubmed publisher
    ..Mechanistically, KLF4 represses the gene encoding the kinase MAP2K7. Our results showed that in murine and pediatric T-ALL, loss of KLF4 leads to aberrant activation of MAP2K7 and of ..
  36. Peng B, Chai Y, Li Y, Liu X, Zhang J. CIP2A overexpression induces autoimmune response and enhances JNK signaling pathway in human lung cancer. BMC Cancer. 2015;15:895 pubmed publisher
    ..Furthermore, the expression level of CIP2A also affected the phosphorylation of the upstream kinase of JNK, MKK4/MKK7. At last, treatment with JNK inhibitor partially abolished CIP2A-induced cell proliferation...
  37. Li Z, Jiang J, Tian L, Li X, Chen J, Li S, et al. A plasma mir-125a-5p as a novel biomarker for Kawasaki disease and induces apoptosis in HUVECs. PLoS ONE. 2017;12:e0175407 pubmed publisher
    ..bioinformatics prediction, miR-125a-5p vector and inhibitor were transfected into HUVECs respectively, to observe MKK7 expression as a potential target gene. Flow cytometry was used to analyze apoptosis...
  38. Lao Y, Yang K, Wang Z, Sun X, Zou Q, Yu X, et al. DeSUMOylation of MKK7 kinase by the SUMO2/3 protease SENP3 potentiates lipopolysaccharide-induced inflammatory signaling in macrophages. J Biol Chem. 2018;293:3965-3980 pubmed publisher
    ..Of note, SENP3 deficiency was associated with impairment in JNK phosphorylation. We found that MKK7, which selectively phosphorylates JNK, is a SENP3 substrate and that SENP3-mediated deSUMOylation of MKK7 may favor ..
  39. Chayama K, Papst P, Garrington T, Pratt J, Ishizuka T, Webb S, et al. Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc Natl Acad Sci U S A. 2001;98:4599-604 pubmed
    ..b>MKK7 is activated in response to cross-linking of FcepsilonRI, and this activation is inhibited by MAP/ERK kinase (MEK) ..
  40. Openshaw R, Thomson D, Penninger J, Pratt J, Morris B. Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline. Psychopharmacology (Berl). 2017;234:293-305 pubmed publisher
    ..Attentional function in mice haploinsufficient for Map2k7 (Map2k7 +/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT)...
  41. Rega C, Russo R, Focà A, Sandomenico A, Iaccarino E, Raimondo D, et al. Probing the interaction interface of the GADD45?/MKK7 and MKK7/DTP3 complexes by chemical cross-linking mass spectrometry. Int J Biol Macromol. 2018;114:114-123 pubmed publisher
    ..GADD45? physically interacts with the JNK kinase, MKK7, inhibiting its activity to enable the survival of cancer cells...
  42. Haun F, Neumann S, Peintner L, Wieland K, Habicht J, Schwan C, et al. Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin. Nat Commun. 2018;9:3524 pubmed publisher
    ..Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim...
  43. Kawaguchi M, Onuchic L, Huang S. Activation of extracellular signal-regulated kinase (ERK)1/2, but not p38 and c-Jun N-terminal kinase, is involved in signaling of a novel cytokine, ML-1. J Biol Chem. 2002;277:15229-32 pubmed
    ..Selective MAP kinase kinase (MEK)1/2 inhibitors, PD98059 and U0126, inhibited, in a dose-dependent manner, ML-1-induced expression of IL-6 and IL-8...
  44. Yoshizawa T, Hammaker D, Sweeney S, Boyle D, Firestein G. Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases. J Immunol. 2008;181:3252-8 pubmed
    ..It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix ..
  45. Sogabe Y, Matsumoto T, Hashimoto T, Kirii Y, Sawa M, Kinoshita T. 5Z-7-Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner. Bioorg Med Chem Lett. 2015;25:593-6 pubmed publisher
    ..g., ERK2 and TAK1) that possess a free cysteine at the gatekeeper-2 position. In addition to this cysteine, MAP2K7 has three other cysteine residues that are candidate for covalent bonding by the inhibitor 5Z7O...
  46. Christensen D, Ejlerskov P, Rasmussen I, Vilhardt F. Reciprocal signals between microglia and neurons regulate α-synuclein secretion by exophagy through a neuronal cJUN-N-terminal kinase-signaling axis. J Neuroinflammation. 2016;13:59 pubmed publisher
    ..Conversely, expression of constitutively active mitogen-activated protein kinase kinase 7 (MKK7)-JNK2 and -JNK3 constructs augment secretion...
  47. Padzik A, Deshpande P, Hollos P, Franker M, Rannikko E, Cai D, et al. KIF5C S176 Phosphorylation Regulates Microtubule Binding and Transport Efficiency in Mammalian Neurons. Front Cell Neurosci. 2016;10:57 pubmed publisher
    ..The same directionality switching is observed with KIF5C(1-560)(WT) in the presence of an active JNK chimera, MKK7-JNK...
  48. He P, Zhang B, Liu D, Bian X, Li D, Wang Y, et al. Hepatitis B Virus X Protein Modulates Apoptosis in NRK-52E Cells and Activates Fas/FasL Through the MLK3-MKK7-JNK3 Signaling Pathway. Cell Physiol Biochem. 2016;39:1433-43 pubmed publisher
    ..Recent studies indicated that HBx induction of apoptosis in hepatic cells depends on activating the MLK3-MKK7-JNKs signaling module, which then up-regulates FasL expression...
  49. Lampard G, Wengier D, Bergmann D. Manipulation of mitogen-activated protein kinase kinase signaling in the Arabidopsis stomatal lineage reveals motifs that contribute to protein localization and signaling specificity. Plant Cell. 2014;26:3358-71 pubmed publisher
    ..MKK4/5/7/9, are capable of perturbing stomatal development and that these kinases comprise two pairs, MKK4/5 and MKK7/9, with both overlapping and divergent functions...
  50. Zhang Z, Li M, Ma X, Zhou S, Ren Z, Qiu Y. GADD45β-I attenuates oxidative stress and apoptosis via Sirt3-mediated inhibition of ER stress in osteoarthritis chondrocytes. Chem Biol Interact. 2018;296:76-82 pubmed publisher
    ..MAPK kinase 7 (MKK7) is a direct upstream kinase that regulates JNK and has been shown to activate JNK specifically under toxic ..
  51. Sundarrajan M, Boyle D, Chabaud Riou M, Hammaker D, Firestein G. Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthritis Rheum. 2003;48:2450-60 pubmed
    ..This novel JNK signalsome is activated in response to IL-1 and migrates to the nucleus. The JNK signalsome represents a new target for therapeutic interventions designed to prevent joint destruction. ..
  52. 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
    ..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...
  53. Lee K, Lee S, Lee H, Lee H, Shin J, Kim N, et al. α-Chaconine isolated from a Solanum tuberosum L. cv Jayoung suppresses lipopolysaccharide-induced pro-inflammatory mediators via AP-1 inactivation in RAW 264.7 macrophages and protects mice from endotoxin shock. Chem Biol Interact. 2015;235:85-94 pubmed publisher
    ..of TGF-β-activated kinase-1 (TAK1), which lies upstream of mitogen-activated protein kinase kinase 7 (MKK7)/Jun N-terminal kinase (JNK) signaling...
  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
    ..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. 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
    ..showing that inhibiting ROCK suppressed the IL-1-induced phosphorylation of MKK4, a known activator of JNK, but not MKK7. Yet, ROCK inhibition had no significant effect on the IL-1-induced phosphorylation of extracellular-signal-..
  56. Guo Y, Wang W, Wang J, Feng J, Wang Q, Jin J, et al. Receptor for activated C kinase 1 promotes hepatocellular carcinoma growth by enhancing mitogen-activated protein kinase kinase 7 activity. Hepatology. 2013;57:140-51 pubmed publisher
    ..protein implicated in the regulation of multiple signaling pathways, could engage in a direct interaction with MKK7, the JNK-specific MAP2K, in human HCC cells...
  57. Zubor P, Hatok J, Moricova P, Kajo K, Kapustova I, Mendelova A, et al. Gene expression abnormalities in histologically normal breast epithelium from patients with luminal type of breast cancer. Mol Biol Rep. 2015;42:977-88 pubmed publisher
    ..05) and BCL2L2, CTSB, ITGB4, JUN, KIT, KLF5, SCGB1D2, SCGB2A1, SERPINE1 (p < 0.01), and EGFR, GABRP, GSN, MAP2K7 and THBS2 (p < 0.001), and GSN, KLK5 (p < 0.0001)...
  58. Zhan X, Stoy H, Kaoud T, Perry N, Chen Q, Perez A, et al. Peptide mini-scaffold facilitates JNK3 activation in cells. Sci Rep. 2016;6:21025 pubmed publisher
    ..Here we demonstrate that this peptide also binds MKK4, MKK7, and ASK1, which are upstream JNK3-activating kinases. This peptide is sufficient to enhance JNK3 activity in cells...
  59. Enomoto A, Suzuki N, Morita A, Ito M, Liu C, Matsumoto Y, et al. Caspase-mediated cleavage of JNK during stress-induced apoptosis. Biochem Biophys Res Commun. 2003;306:837-42 pubmed
    ..Altogether, our results demonstrated that p54 JNKs, at least JNK1beta2 and JNK2beta2, were new selective targets of caspases in JNK splicing variants, and suggested that the p52 form could serve as a marker of apoptosis. ..
  60. Li Z, Meng D, Li G, Xu J, Tian K, Li Y. Celecoxib Combined with Diacerein Effectively Alleviates Osteoarthritis in Rats via Regulating JNK and p38MAPK Signaling Pathways. Inflammation. 2015;38:1563-72 pubmed publisher
    ..DC significantly inactivated the c-Jun N-terminal kinases (JNK) signaling pathway by the inhibition of MEKK1 and MKK7, as detected by Western blot analysis...
  61. 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
    ..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%...
  62. Tu Z, Lee F. Subdomain VIII is a specificity-determining region in MEKK1. J Biol Chem. 2003;278:48498-505 pubmed
    ..Collectively these results provide evidence that subdomain VIII of MEKK1 is involved not only in binding to, but also in discrimination of, protein substrates. ..
  63. Karin M. Whipping NF-κB to Submission via GADD45 and MKK7. Cancer Cell. 2014;26:447-9 pubmed publisher
    ..In this issue of Cancer Cell, Tornatore and colleagues solve this problem by targeting the GADD45:MKK7 module mediating NF-κB-induced survival of multiple myelomas.
  64. Neoh C, Wu W, Dai G, Su J, Liu C, Su T, et al. Flaccidoxide-13-Acetate Extracted from the Soft Coral Cladiella kashmani Reduces Human Bladder Cancer Cell Migration and Invasion through Reducing Activation of the FAK/PI3K/AKT/mTOR Signaling Pathway. Molecules. 2017;23: pubmed publisher
    ..mTOR), p-mTOR, Ras homolog gene family, member A (Rho A), Ras, mitogen-activated protein kinase kinase 7 (MKK7) and mitogen-activated protein kinase kinase kinase 3 (MEKK3), and increased the expressions of tissue inhibitor of ..
  65. Yoon J, Cho H, Lee J, Lee H, Jun S, Lee J, et al. Novel TRAIL sensitizer Taraxacum officinale F.H. Wigg enhances TRAIL-induced apoptosis in Huh7 cells. Mol Carcinog. 2016;55:387-96 pubmed publisher
    ..of the TOR signaling pathway regulator-like (TIPRL) protein caused TRAIL-induced apoptosis by activation of the MKK7-c-Jun N-terminal Kinase (JNK) pathway through disruption of the MKK7-TIPRL interaction...
  66. 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...
  67. Ikeda A, Hasegawa K, Masaki M, Moriguchi T, Nishida E, Kozutsumi Y, et al. Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway. J Biochem. 2001;130:773-81 pubmed
    ..LZK directly phosphorylated and activated MKK7, one of the two MAPKKs in the JNK/SAPK pathway, to a comparable extent to a constitutive active form of MEKK1 (..
  68. Marino N, Collins J, Shen C, Caplen N, Merchant A, Gökmen Polar Y, et al. Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines. Clin Exp Metastasis. 2014;31:771-86 pubmed publisher
    ..siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was ..
  69. Guo M, Wei J, Zhou Y, Qin Q. MKK7 confers different activities to viral infection of Singapore grouper iridovirus (SGIV) and nervous necrosis virus (NNV) in grouper. Fish Shellfish Immunol. 2016;57:419-427 pubmed publisher
    Mitogen-activated protein kinase 7 (MKK7) is one of the major stress-activated protein kinase (SAPK)-activating kinases in response to environmental or physiological stimuli...
  70. Yang H, Kircher D, Kim K, Grossmann A, Vanbrocklin M, Holmen S, et al. Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma. Oncogene. 2017;36:3842-3851 pubmed publisher
    ..Mitogen-activated protein kinase kinase (MEK) mutations are found in primary melanomas and frequently reported in BRAF melanomas that develop resistance to ..
  71. Alhoshani A, Hafez M, Husain S, Al sheikh A, Alotaibi M, Al Rejaie S, et al. Protective effect of rutin supplementation against cisplatin-induced Nephrotoxicity in rats. BMC Nephrol. 2017;18:194 pubmed publisher
    ..and for the study the gene expression of c-Jun N-terminal kinases (JNK), Mitogen-activated protein kinase 4 (MKK4), MKK7, P38 mitogen-activated protein kinases (P38), tumor necrosis factors alpha (TNF-α), TNF Receptor-Associated Factor ..
  72. 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...
  73. Song I, Jun S, Na H, Kim H, Jung S, Ha G, et al. Inhibition of MKK7-JNK by the TOR signaling pathway regulator-like protein contributes to resistance of HCC cells to TRAIL-induced apoptosis. Gastroenterology. 2012;143:1341-1351 pubmed publisher
    ..transferase pull-down analyses to determine interactions among mitogen-activated protein kinase kinase 7 (MKK7 or MAP2K7), TIPRL, and the protein phosphatase type 2A (PP2Ac). We studied the effects of TIPRL in tumor xenografts in mice...
  74. 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...
  75. Yushak M, Chapman P, Robert C, Kudchadkar R. Systemic Therapy Options for Patients With Unresectable Melanoma. Am Soc Clin Oncol Educ Book. 2017;37:661-672 pubmed publisher
    ..Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed. Combination BRAF and MEK inhibition has also been shown to improve overall survival in patients with V600E-mutated melanoma...
  76. Wengier D, Lampard G, Bergmann D. Dissection of MAPK signaling specificity through protein engineering in a developmental context. BMC Plant Biol. 2018;18:60 pubmed publisher
    ..We artificially activated the MAPK cascade using MKK7, another MKK that can modulate stomatal development, and found that inhibition of stomatal development is still ..
  77. Yang J. Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest. Biochem Biophys Res Commun. 2002;297:105-10 pubmed
    ..The mechanisms by which ZAK activity is regulated are not well understood. Co-expression of dominant-negative MKK7 but not MKK4 and ZAK significantly attenuates JNK/SAPK activation...
  78. Cooper S, Sandhu H, Hussain A, Mee C, Maddock H. Involvement of mitogen activated kinase kinase 7 intracellular signalling pathway in Sunitinib-induced cardiotoxicity. Toxicology. 2018;394:72-83 pubmed publisher
    ..Mitogen activated kinase kinase 7 (MKK7) is involved in the development of cardiac injury and is a component of the c-Jun N-terminal kinase (JNK) signal ..
  79. 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
    ..Both DLK and MLK3 associated with, phosphorylated, and activated MKK7 in vitro. Unlike MLK3, however, DLK did not phosphorylate or activate recombinant MKK4 in vitro...
  80. Jin U, Karki K, Kim S, Safe S. Inhibition of pancreatic cancer Panc1 cell migration by omeprazole is dependent on aryl hydrocarbon receptor activation of JNK. Biochem Biophys Res Commun. 2018;501:751-757 pubmed publisher
    ..of Panc1 cell invasion was dependent on Jun-N-terminal kinase (JNK) and mitogen-activated kinase kinase 7 (MKK7)...
  81. Lee H, Back K. Mitogen-activated protein kinase pathways are required for melatonin-mediated defense responses in plants. J Pineal Res. 2016;60:327-35 pubmed publisher
    ..Using an array of MAP kinase kinase (MKK) knockout mutants, we found that four MKKs, namely MKK4, MKK5, MKK7, and MKK9, are responsible for the activation of MPK3 and MPK6 by melatonin, indicating that melatonin-mediated ..
  82. 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
    ..These data suggest that MKK4 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase Itch, which has a fundamental role in the mechanism that controls MKK4 protein levels. ..
  83. 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...
  84. Huang Y, Zhou B, Wernig M, Sudhof T. ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and A? Secretion. Cell. 2017;168:427-441.e21 pubmed publisher ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases...
  85. Woo V, Cheng C, Duraikannu A, Chandrasekhar A, Purdy K, Martinez J, et al. Caspase-6 is a Dispensable Enabler of Adult Mammalian Axonal Degeneration. Neuroscience. 2018;371:242-253 pubmed publisher
    ..Serial analysis of cutaneous ear pinna axons in live mice provides a useful and novel model of axonal integrity. ..
  86. Wang D, Pan Y, Liu B, Dai L. Cav-1 promotes atherosclerosis by activating JNK-associated signaling. Biochem Biophys Res Commun. 2018;503:513-520 pubmed publisher
    ..Also, the activity of mitogen-activated protein kinases 7/c-Jun-N-terminal kinase (MKK7/JNK) signaling was decreased by Cav-1-/-...
  87. Zhang H, Wu W, Du Y, Santos S, Conrad S, Watson J, et al. Hsp90/p50cdc37 is required for mixed-lineage kinase (MLK) 3 signaling. J Biol Chem. 2004;279:19457-63 pubmed
    ..Our findings reveal that Hsp90/p50(cdc37) also regulates protein kinases involved in apoptotic signaling. ..
  88. Tian J, Locker J. Gadd45 in the liver: signal transduction and transcriptional mechanisms. Adv Exp Med Biol. 2013;793:69-80 pubmed publisher
    ..Gadd45β binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2...
  89. Yue J, López J. JNK does not regulate meiotic progression in Xenopus oocytes: The strange case of pJNK and pERK. Dev Biol. 2016;416:42-51 pubmed publisher
    ..Moreover, a constitutively active MKK7, which specifically activates the JNK signaling pathway and induces phosphorylation of the p40 and p49 isoforms, ..
  90. Xie S, Li J, Chen H, Tan Y, Liu S, Zhang Y, et al. Inhibition of the JNK/MAPK signaling pathway by myogenesis-associated miRNAs is required for skeletal muscle development. Cell Death Differ. 2018;25:1581-1597 pubmed publisher
    ..pathway by repressing multiple factors for the phosphorylation of the JNK/MAPK pathway, including MEKK1, MEKK2, MKK7, and c-Jun but not JNK protein itself, and as a result, expression of transcriptional factor MyoD and mamiRs were ..
  91. Gross E, Callow M, Waldbaum L, Thomas S, Ruggieri R. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. J Biol Chem. 2002;277:13873-82 pubmed
    ..kidney cells, we found that MRK-beta preferentially activates ERK6/p38gamma via MKK3/MKK6 and JNK through MKK4/MKK7. We also show that expression of wild type MRK increases the cell population in the G(2)/M phase of the cell cycle, ..