Gene Symbol: MKK7
Description: mitogen-activated protein kinase kinase 7
Alias: 5930412N11Rik, JNKK 2, Jnkk2, MAPKK 7, MEK 7, Mapkk7, Mek7, Mkk7, Prkmk7, sek2, dual specificity mitogen-activated protein kinase kinase 7, JNK kinase 2, JNK-activating kinase 2, MAP kinase kinase 7, MAPK/ERK kinase 7, c-Jun N-terminal kinase kinase 2, map2k7, protein kinase, mitogen activated, kinase 7
Species: mouse
Products:     MKK7

Top Publications

  1. Harr B, Voolstra C, Heinen T, Baines J, Rottscheidt R, Ihle S, et al. A change of expression in the conserved signaling gene MKK7 is associated with a selective sweep in the western house mouse Mus musculus domesticus. J Evol Biol. 2006;19:1486-96 pubmed
    ..survey between subspecies of the Mus musculus complex, we identified the mitogen-activated protein-kinase-kinase MKK7 as a candidate for change in gene expression...
  2. Moriguchi T, Toyoshima F, Masuyama N, Hanafusa H, Gotoh Y, Nishida E. A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses. EMBO J. 1997;16:7045-53 pubmed
    ..Here we have cloned, identified and characterized a novel member of the mammalian MAPKKs, designated MKK7. MKK7 is most similar to the mediator of morphogenesis, hemipterous (hep), in Drosophila...
  3. 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
    ..To elucidate the physiological functions of MKK7, we used Nestin-Cre to generate a novel mouse model in which the mkk7 gene was specifically deleted in the nervous ..
  4. 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...
  5. 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
    ..with a JNK activator, MAP kinase kinase (MKK)7, in a TNFalpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFbeta-activated kinase 1...
  6. Jaeschke A, Davis R. Metabolic stress signaling mediated by mixed-lineage kinases. Mol Cell. 2007;27:498-508 pubmed
    ..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...
  7. 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. ..
  8. Dong C, Yang D, Tournier C, Whitmarsh A, Xu J, Davis R, et al. JNK is required for effector T-cell function but not for T-cell activation. Nature. 2000;405:91-4 pubmed
    ..However, production of effector T-cell cytokines did require JNK. Thus, JNK is necessary for T-cell differentiation but not for naive T-cell activation. ..
  9. 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 ..

More Information


  1. 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...
  2. Wada T, Joza N, Cheng H, Sasaki T, Kozieradzki I, Bachmaier K, et al. MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nat Cell Biol. 2004;6:215-26 pubmed
    ..Here we show that genetic inactivation of the stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in embryonic lethality and impaired proliferation of hepatocytes...
  3. ElAli A, Hermann D. Apolipoprotein E controls ATP-binding cassette transporters in the ischemic brain. Sci Signal. 2010;3:ra72 pubmed publisher
    ..ApoE regulated the postischemic abundance of ABCB1 and ABCC1, thereby controlling drug accumulation in the ischemic brain. Our data suggest that inhibition of ApoE signaling may enable improved delivery of drugs to the brain...
  4. Winchester C, Ohzeki H, Vouyiouklis D, Thompson R, Penninger J, Yamagami K, et al. Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. Hum Mol Genet. 2012;21:4910-21 pubmed publisher
    ..In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7-a kinase activated by glutamatergic activity...
  5. 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. ..
  6. 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
    ..MKK4 and MKK7 are upstream kinases of the mitogen-activated protein kinases (MAPKs), responsible for channeling physiological and ..
  7. Schramek D, Kotsinas A, Meixner A, Wada T, Elling U, Pospisilik J, et al. The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nat Genet. 2011;43:212-9 pubmed publisher
    ..Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces ..
  8. 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
    ..In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not ..
  9. Yao Z, Diener K, Wang X, Zukowski M, Matsumoto G, Zhou G, et al. Activation of stress-activated protein kinases/c-Jun N-terminal protein kinases (SAPKs/JNKs) by a novel mitogen-activated protein kinase kinase. J Biol Chem. 1997;272:32378-83 pubmed
    ..We have isolated a cDNA encoding a novel protein kinase that has significant homology to MKKs. The novel kinase MKK7 has a nucleotide sequence that encodes an open reading frame of 347 amino acids with 11 kinase subdomains...
  10. Lee S, Boyle D, Berdeja A, Firestein G. Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthritis Res Ther. 2012;14:R38 pubmed publisher
    ..Cytokine-induced JNK activation is strictly dependent on the mitogen-activated protein kinase kinase 7 (MKK7) in fibroblast-like synoviocytes (FLS)...
  11. Feltrin D, Fusco L, Witte H, Moretti F, Martin K, Letzelter M, et al. Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation. PLoS Biol. 2012;10:e1001439 pubmed publisher
    ..screen for neurite-enriched mRNAs and identified an mRNA that encodes mitogen-activated protein kinase kinase 7 (MKK7), a MAP kinase kinase (MAPKK) for Jun kinase (JNK)...
  12. Kelkar N, Standen C, Davis R. Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Mol Cell Biol. 2005;25:2733-43 pubmed
    ..The JIP4 scaffold protein therefore appears to be a new component of the p38 MAP kinase signaling pathway. ..
  13. Petrich B, Eloff B, Lerner D, Kovacs A, Saffitz J, Rosenbaum D, et al. Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J Biol Chem. 2004;279:15330-8 pubmed
    ..These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease. ..
  14. 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. ..
  15. Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M. Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway. J Biol Chem. 2002;277:23919-26 pubmed
    ..protein kinase (MAPK) phosphatase (MKP) family that interacts physically with the MAPK kinase (MAPKK) MKK7, a c-Jun N-terminal kinase (JNK) activator, and inactivates the MAPK JNK pathway...
  16. 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
    ..The CARMA1-binding site in ADAP is critical for mitogen-activated protein (MAP) kinase kinase 7 (MKK7) phosphorylation and recruitment to the protein kinase C ? (PKC?) signalosome and subsequent c-Jun kinase (JNK)-..
  17. Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Nishina H, et al. Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. J Bone Miner Res. 2002;17:612-21 pubmed
    ..using an adenovirus vector carrying the dominant negative 1kappaB kinase 2 gene (AxIKK2DN) or dominant negative MKK7 gene (AxMKK7DN)...
  18. 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)...
  19. 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. ..
  20. Derradji H, Bekaert S, De Meyer T, Jacquet P, Abou El Ardat K, Ghardi M, et al. Ionizing radiation-induced gene modulations, cytokine content changes and telomere shortening in mouse fetuses exhibiting forelimb defects. Dev Biol. 2008;322:302-13 pubmed publisher
    ..Secondly, our results showed overexpression of MKK3 and MKK7 (members of the stress-activated MAP kinase family) within the malformed fetuses...
  21. 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
  22. Liu W, Zi M, Chi H, Jin J, Prehar S, Neyses L, et al. Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload. J Mol Cell Cardiol. 2011;50:702-11 pubmed publisher
    ..Mitogen-activated protein kinase kinase 7 (MKK7) is a critical component of stress-activated MAP kinase signaling pathway...
  23. 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
    ..These results provide the first genetic link between stress-responsive kinases and organogenesis in mammals and indicate that SEK1 provides a crucial and specific survival signal for hepatocytes. ..
  24. Foltz I, Gerl R, Wieler J, Luckach M, Salmon R, Schrader J. Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. J Biol Chem. 1998;273:9344-51 pubmed
    ..the cloning of a novel human activator of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 7 (MKK7)...
  25. Zhan X, Kaoud T, Kook S, Dalby K, Gurevich V. JNK3 enzyme binding to arrestin-3 differentially affects the recruitment of upstream mitogen-activated protein (MAP) kinase kinases. J Biol Chem. 2013;288:28535-47 pubmed publisher
    ..However, full JNK3?2 activation requires phosphorylation by both MKK4 and MKK7. Using purified proteins we show that arrestin-3 directly interacts with MKK7 and promotes JNK3?2 phosphorylation ..
  26. 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. ..
  27. 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
    ..In sum, our findings uncover a regulatory role played by the MKK4/7-JNK1/2 pathway in cytoskeleton reorganization during VACV infection...
  28. 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...
  29. 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
    ..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...
  30. 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...
  31. 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. ..
  32. Uchida Y, Osaki T, Yamasaki T, Shimomura T, Hata S, Horikawa K, et al. Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock. J Biol Chem. 2012;287:8318-26 pubmed publisher
    The stress kinase mitogen-activated protein kinase kinase 7 (MKK7) is a specific activator of c-Jun N-terminal kinase (JNK), which controls various physiological processes, such as cell proliferation, apoptosis, differentiation, and ..
  33. Holland P, Suzanne M, Campbell J, Noselli S, Cooper J. MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. J Biol Chem. 1997;272:24994-8 pubmed
    ..We have identified MKK7, a murine homolog of Hep. MKK7 functionally rescues hep mutant flies...
  34. 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
    ..MKK4(-/-) and MKK4(-/-)/7(-/-) murine embryonic fibroblast cells, we examined differential employment of MKK4 and MKK7 by scaffold proteins Axin, Dvl, and Epstein-Barr virus latent membrane protein-1 (LMP-1) in mediating JNK ..
  35. Nakamura K, Johnson G. Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling. Mol Cell Biol. 2007;27:4566-77 pubmed
    ..C-terminal moiety, including the acidic cluster of the MEKK2 PB1 domain, is not required for MEK5 binding and binds MKK7. Quiescent MEKK2 preferentially binds MEK5, and MEKK2 activation results in ERK5 activation...
  36. Akiyama S, Yonezawa T, Kudo T, Li M, Wang H, Ito M, et al. Activation mechanism of c-Jun amino-terminal kinase in the course of neural differentiation of P19 embryonic carcinoma cells. J Biol Chem. 2004;279:36616-20 pubmed
    ..These results suggest that two distinct TAK1-MKK4-JNK signaling pathways are independently activated at the different intracellular locations and may participate in the regulation of the neural differentiation of P19 cells. ..