Gene Symbol: MKK6
Description: mitogen-activated protein kinase kinase 6
Alias: MAPKK6, MEK6, MKK6, PRKMK6, SAPKK-3, SAPKK3, dual specificity mitogen-activated protein kinase kinase 6, MAPK/ERK kinase 6, MAPKK 6, MEK 6, SAPK kinase 3, protein kinase, mitogen-activated, kinase 6 (MAP kinase kinase 6), stress-activated protein kinase kinase 3
Species: human
Products:     MKK6

Top Publications

  1. Singhirunnusorn P, Suzuki S, Kawasaki N, Saiki I, Sakurai H. Critical roles of threonine 187 phosphorylation in cellular stress-induced rapid and transient activation of transforming growth factor-beta-activated kinase 1 (TAK1) in a signaling complex containing TAK1-binding protein TAB1 and TAB2. J Biol Chem. 2005;280:7359-68 pubmed
    ..These results indicate critical roles of Thr-187 phosphorylation in the stress-induced rapid and transient activation of TAK1 in a signaling complex containing TAB1 and TAB2. ..
  2. Shambharkar P, Blonska M, Pappu B, Li H, You Y, Sakurai H, et al. Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways. EMBO J. 2007;26:1794-805 pubmed
    ..Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKalpha/beta and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation. ..
  3. Wang X, McGowan C, Zhao M, He L, Downey J, Fearns C, et al. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000;20:4543-52 pubmed
    ..Activation of the MKK6-p38gamma cascade is sufficient to induce G(2) arrest in cells, and expression of dominant negative alleles of MKK6 ..
  4. Wang C, Deng L, Hong M, Akkaraju G, Inoue J, Chen Z. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001;412:346-51 pubmed
    ..Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination...
  5. Xia Z, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009;461:114-9 pubmed publisher
    ..These results indicate that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a new mechanism of protein kinase regulation. ..
  6. Sullivan I, Riera P, Andrés M, Altes A, Majem M, Blanco R, et al. Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients. Angiogenesis. 2019;: pubmed publisher
  7. Rothammer S, Seichter D, Forster M, Medugorac I. A genome-wide scan for signatures of differential artificial selection in ten cattle breeds. BMC Genomics. 2013;14:908 pubmed publisher
    ..Based on the confirmation process and literature search we deduce that XP-EHH is able to uncover numerous artificial selection targets in subpopulations of domesticated animals. ..
  8. Li Z, Li N, Shen L. MAP2K6 is associated with radiation resistance and adverse prognosis for locally advanced nasopharyngeal carcinoma patients. Cancer Manag Res. 2018;10:6905-6912 pubmed publisher
    ..030). The present study indicated that MAP2K6 was correlated with radioresistance, and the elevated expression of MAP2K6 predicted poor prognosis in NPC patients. MAP2K6 may be a new therapy target for radioresistance of NPC. ..
  9. Wu X, Sun S. Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK. EMBO Rep. 2007;8:510-5 pubmed
    ..These findings show a pathological mechanism of IKK activation by Tax and provide an example for how IKK is persistently activated in cancer cells. ..

More Information

Publications172 found, 100 shown here

  1. Chung B, Stadion M, Schulz N, Jain D, Scherneck S, Joost H, et al. The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice. Diabetologia. 2015;58:2403-13 pubmed publisher
    ..However, it does not induce type 2 diabetes, suggesting that the diabetogenic effect of the Zfp69 locus requires synergy with other as yet unidentified genes. ..
  2. Lian K, Gao F, Sun T, van Wersch R, Ao K, Kong Q, et al. MKK6 Functions in Two Parallel MAP Kinase Cascades in Immune Signaling. Plant Physiol. 2018;178:1284-1295 pubmed publisher
    ..cascade promotes basal resistance against pathogens and is guarded by the NB-LRR protein SUMM2, whereas the ANPs-MKK6-MPK4 cascade plays an essential role in cytokinesis...
  3. Qu F, Tang J, Liao J, Chen B, Song P, Luo W, et al. Mitogen-activated protein kinase kinase 6 is involved in the immune response to bacterial di-/tripeptide challenge in grass carp Ctenopharyngodon idella. Fish Shellfish Immunol. 2019;84:795-801 pubmed publisher
    Mitogen-activated protein kinase kinase 6 (MKK6) is an essential component of the p38MAPK signaling pathway, which is involved in the modulation of inflammation, cell apoptosis and survival responses in mammals...
  4. Frevel M, Bakheet T, Silva A, Hissong J, Khabar K, Williams B. p38 Mitogen-activated protein kinase-dependent and -independent signaling of mRNA stability of AU-rich element-containing transcripts. Mol Cell Biol. 2003;23:425-36 pubmed
    ..Finally, the identification of the p38-dependent upstream activator MAP kinase kinase 6 as a member of this group identifies a positive feedback loop regulating macrophage signaling via p38 MAP kinase-dependent transcript stabilization. ..
  5. 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. ..
  6. Xie X, Liu K, Liu F, Chen H, Wang X, Zu X, et al. Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo. Cancer Lett. 2018;442:126-136 pubmed publisher
    ..indicate that gossypetin strongly attenuates the MKK3/6-p38 signaling pathway by directly inhibiting MKK3 and MKK6 protein kinase activity in vitro...
  7. Kajino T, Ren H, Iemura S, Natsume T, Stefansson B, Brautigan D, et al. Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. J Biol Chem. 2006;281:39891-6 pubmed
    ..Our results demonstrate that PP6 specifically down-regulates TAK1 through dephosphorylation of Thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via TAK1 signaling pathways. ..
  8. Smyk M, Roeder E, Cheung S, Szafranski P, Stankiewicz P. A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures. Am J Med Genet A. 2015;167A:1842-50 pubmed publisher
  9. Liu K, Zhang C, Li B, Xie W, Zhang J, Nie X, et al. Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression. Cell Rep. 2018;23:838-851 pubmed publisher
    ..Here, we report that TRIM9 short isoform (TRIM9s) potentiates p38 signaling by stabilizing MKK6. Mechanistic studies revealed that TRIM9s promotes the K63-linked ubiquitination of MKK6 at Lys82, thus inhibiting ..
  10. Stein B, Brady H, Yang M, Young D, Barbosa M. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996;271:11427-33 pubmed
    ..A novel mitogen-activated protein kinase kinase, MEK6, was cloned and characterized. The complete MEK6 cDNA was isolated by polymerase chain reaction...
  11. McMullen M, Bryant P, Glembotski C, Vincent P, Pumiglia K. Activation of p38 has opposing effects on the proliferation and migration of endothelial cells. J Biol Chem. 2005;280:20995-1003 pubmed
    ..the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38...
  12. Fanous S, Guez Barber D, Goldart E, Schrama R, Theberge F, Shaham Y, et al. Unique gene alterations are induced in FACS-purified Fos-positive neurons activated during cue-induced relapse to heroin seeking. J Neurochem. 2013;124:100-8 pubmed publisher
  13. Lopes L, Tesser Gamba F, Petrilli A, de Seixas Alves M, Garcia Filho R, Toledo S. MAPK pathways regulation by DUSP1 in the development of osteosarcoma: Potential markers and therapeutic targets. Mol Carcinog. 2017;56:1630-1641 pubmed publisher
    ..These results suggest that members of MAPK family may be possible prognostic markers in OS and DUSP1 has a relevant role in the OS pathogenesis and can be an attractive therapeutic target in new strategies of OS treatment. ..
  14. Fridley B, Dai J, Raghavan R, Li Q, Winham S, Hou X, et al. Transcriptomic Characterization of Endometrioid, Clear Cell, and High-Grade Serous Epithelial Ovarian Carcinoma. Cancer Epidemiol Biomarkers Prev. 2018;27:1101-1109 pubmed publisher
    ..i>Cancer Epidemiol Biomarkers Prev; 27(9); 1101-9. ©2018 AACR. ..
  15. Silva A, Whitmore M, Xu Z, Jiang Z, Li X, Williams B. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. J Biol Chem. 2004;279:37670-6 pubmed
    ..We found that the p38 MAPK activator MKK6, but not its close relatives MKK3 or MKK4, exhibited an increased affinity for PKR following the exposure of cells ..
  16. Kaur R, Liu X, Gjoerup O, Zhang A, Yuan X, Balk S, et al. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005;280:3323-30 pubmed
    ..protein (MAP) kinase antagonist and could be strongly stimulated by constitutively active MAP kinase kinase 6 (MKK6), an upstream activator of p38 MAP kinases...
  17. Ding N, Wang F, Han Y, Xiao H, Xu L, She S. Mitogen-activated protein kinase kinase 6 mediates mechanical stretch-induced high-mobility group box 1 protein expression in pulmonary alveolar epithelial cells. J Trauma Acute Care Surg. 2012;72:162-8 pubmed publisher
    ..The aim of this study was to explore the role of mitogen-activated protein kinase kinase 6 (MKK6) in the HMGB1 expression in pulmonary alveolar epithelial cells induced by mechanical stretch...
  18. Greenblatt M, Kim J, Oh H, Park K, Choo M, Sano Y, et al. p38α MAPK is required for tooth morphogenesis and enamel secretion. J Biol Chem. 2015;290:284-95 pubmed publisher
    ..Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase ..
  19. Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997;16:3563-71 pubmed
    ..SAPK4 was activated in vitro by SKK3 (also called MKK6) or when co-transfected with SKK3 into COS cells...
  20. 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. ..
  21. Leem Y, Jeong H, Kim H, Koh J, Kang K, Bae G, et al. Cdo Regulates Surface Expression of Kir2.1 K+ Channel in Myoblast Differentiation. PLoS ONE. 2016;11:e0158707 pubmed publisher
    ..The expression of a constitutively active form of the upstream kinase for p38MAPK, MKK6(EE) can restore Kir2...
  22. Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000;352 Pt 3:739-45 pubmed
    ..the study of LF proteolytic specificity to all known MAPKK family members and found that LF also cleaves MKK4, MKK6 and MKK7, but not MEK5. The peptide bonds hydrolysed by LF within all MAPKKs were identified...
  23. Matsumoto T, Kinoshita T, Matsuzaka H, Nakai R, Kirii Y, Yokota K, et al. Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state. J Biochem. 2012;151:541-9 pubmed publisher
    ..AH1 and AH2 were found to enclose the ?-phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices. ..
  24. Enslen H, Raingeaud J, Davis R. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998;273:1741-8 pubmed
    ..The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms, while MKK3 ..
  25. Lazar A, Coll A, Dobnik D, Baebler S, Bedina Zavec A, Zel J, et al. Involvement of potato (Solanum tuberosum L.) MKK6 in response to potato virus Y. PLoS ONE. 2014;9:e104553 pubmed publisher
    ..These data together provide further insight into the StMKK6 signalling module and its involvement in plant defence. ..
  26. Jiang X, Guo X, Xu X, Teng M, Huang C, Zhang D, et al. Hypoxia regulates CD9-mediated keratinocyte migration via the P38/MAPK pathway. Sci Rep. 2014;4:6304 pubmed publisher
    ..SB203580, a p38/MAPK inhibitor, increased CD9 expression and inhibited keratinocyte migration under hypoxia, while MKK6 (Glu) overexpression decreased CD9 expression and promoted hypoxic keratinocyte migration...
  27. Grimsey N, Aguilar B, Smith T, Le P, Soohoo A, Puthenveedu M, et al. Ubiquitin plays an atypical role in GPCR-induced p38 MAP kinase activation on endosomes. J Cell Biol. 2015;210:1117-31 pubmed publisher
    ..TAB2 associated with TAB1, which induced p38 activation independent of MKK3 and MKK6. The P2Y1 purinergic GPCR also stimulated p38 activation via NEDD4-2-mediated ubiquitination and TAB1-TAB2...
  28. Miranda P, De Palma G, Serkis V, Lu J, Louis Auguste M, McCarville J, et al. High salt diet exacerbates colitis in mice by decreasing Lactobacillus levels and butyrate production. Microbiome. 2018;6:57 pubmed publisher
    ..and protective short-chain fatty acid production, as well as changes in host immune status. We hypothesize that these changes alter gut immune homeostasis and lead to increased vulnerability to inflammatory insults. ..
  29. Li Z, Fu J, Li N, Shen L. Quantitative proteome analysis identifies MAP2K6 as potential regulator of LIFR-induced radioresistance in nasopharyngeal carcinoma cells. Biochem Biophys Res Commun. 2018;505:274-281 pubmed publisher
    ..Further, MAP2K6 kinase activity is required to activate LIFR/p70S6K signaling and to confer pro-survival effect on NPC cells. In conclusion, MAP2K6 might be an important regulator of LIFR-induced radioresistance in NPC. ..
  30. Kumar S, Jiang M, Adams J, Lee J. Pyridinylimidazole compound SB 203580 inhibits the activity but not the activation of p38 mitogen-activated protein kinase. Biochem Biophys Res Commun. 1999;263:825-31 pubmed
    ..Identical results were obtained when the p38 MAPK cascade was partially reconstituted in vitro. Thus, our data clearly indicate that SB 203580 specifically inhibits the activity of p38 MAPK but not its activation by upstream MAPKK. ..
  31. 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
    ..MKK3, MKK4 and MKK6 all show a strong preference for phosphorylation of the tyrosine residue of the Thr-Gly-Tyr motifs in their known ..
  32. 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. ..
  33. Fernandes A, Bian Q, Jiang J, Thomas C, Taylor A, Pereira P, et al. Proteasome inactivation promotes p38 mitogen-activated protein kinase-dependent phosphatidylinositol 3-kinase activation and increases interleukin-8 production in retinal pigment epithelial cells. Mol Biol Cell. 2009;20:3690-9 pubmed publisher this cascade includes proteasome inactivation, activation of mitogen-activated protein kinase kinase (MKK)3/MKK6, activation of p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor phosphorylation, ..
  34. Sturchler E, Feurstein D, McDonald P, Duckett D. Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry. 2010;49:4094-102 pubmed publisher
    ..In response to oxidative stress, ASK1 activates the cell death-associated p38 MAPK pathway by phosphorylating MKK6. Here, we investigated the regulation of oxidative stress-induced ASK1-catalyzed phosphorylation of MKK6...
  35. Coulthard L, Taylor J, Eyre S, Robinson J, Wilson A, Isaacs J, et al. Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis. 2011;70:98-103 pubmed publisher
    ..These encoded proteins both upstream (MKK6) and downstream (MAPKAPK2, MSK1, MSK2) of p38, and MAPK14, the p38-? isoform of p38 MAPK...
  36. Gupta P, Das P, Ukil A. Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by Toll-like receptor-dependent canonical and noncanonical p38 activation. Antimicrob Agents Chemother. 2015;59:2531-9 pubmed publisher studies with dominant-negative (DN) constructs revealed mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 as the immediate upstream regulators of p38...
  37. Lee C, Choi S, Kim J, Kim S, Yoon K, Oh J, et al. Overexpression of prohibitin-1 inhibits RANKL-induced activation of p38-Elk-1-SRE signaling axis blocking MKK6 activity. Biochem Biophys Res Commun. 2015;463:1028-33 pubmed publisher
    ..Anti-osteoclastogenic action of PHB was significantly inhibited by constitutively active forms of MKK6, but not Elk-1...
  38. Rasmussen M, Lyskjær I, Jersie Christensen R, Tarpgaard L, Primdal Bengtson B, Nielsen M, et al. miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells. Nat Commun. 2016;7:12436 pubmed publisher
    ..Our study shows that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p. ..
  39. Pietrzak J, Spickett C, Płoszaj T, Virag L, Robaszkiewicz A. PARP1 promoter links cell cycle progression with adaptation to oxidative environment. Redox Biol. 2018;18:1-5 pubmed publisher
    ..In summary, cell cycle controlled PARP1 transcription helps cells to adapt to a pro-oxidant redox shift. ..
  40. Luo C, Chen H, Wang Y, Lin G, Li C, Tan L, et al. Protective effect of coptisine free base on indomethacin-induced gastric ulcers in rats: Characterization of potential molecular mechanisms. Life Sci. 2018;193:47-56 pubmed publisher
    ..heme oxygenase-1 (HO-1), while significantly decreased the expression of mitogen activated protein Kinase Kinase 6 (MKK6) and translocation of p38 mitogen-activated protein kinase (p38 MAPK)...
  41. 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. Overall, these results indicate that BSK1 regulates plant immunity by phosphorylating MAPKKK5 and suggest a direct ..
  42. Hori T, Saito K, Moore R, Flake G, Negishi M. Nuclear Receptor CAR Suppresses GADD45B-p38 MAPK Signaling to Promote Phenobarbital-induced Proliferation in Mouse Liver. Mol Cancer Res. 2018;16:1309-1318 pubmed publisher
    ..entails CAR binding and inhibition of the growth arrest and DNA-damage-inducible 45 beta (GADD45B)-MAPK kinase 6 (MKK6) scaffold to repress phosphorylation of p38 MAPK...
  43. Lin S, Liu K, Zhang Y, Jiang M, Lu R, Folts C, et al. Pharmacological targeting of p38 MAP-Kinase 6 (MAP2K6) inhibits the growth of esophageal adenocarcinoma. Cell Signal. 2018;51:222-232 pubmed publisher
    ..Ouabain suppresses the proliferation of EAC cells through downregulation of p38 MAP-Kinase 6 (MAP2K6, also known as MKK6). Consistently, shRNA-mediated knockdown of MKK6 reduced the proliferation of EAC cells and tumor growth...
  44. Pham H, Vincenti R, Slice L. COX-2 promoter activation by AT1R-Gq-PAK-p38beta signaling in intestinal epithelial cells. Biochim Biophys Acta. 2008;1779:408-13 pubmed publisher
    ..Expression of constitutively active MKK6 EE but not MKK3 EE induced the COX-2 and Gal4-CREB promoters via p38MAPK...
  45. Stramucci L, Pranteda A, Bossi G. Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer. Cancers (Basel). 2018;10: pubmed publisher
    ..In this review, we summarize the delicate relationship among p53 mutational status, MKK3/MKK6 and the downstream activated master kinase p38MAPK, dissecting a finely-tuned crosstalk, in a potentially cell-..
  46. 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. ..
  47. Nagaleekar V, Sabio G, Aktan I, Chant A, Howe I, Thornton T, et al. Translational control of NKT cell cytokine production by p38 MAPK. J Immunol. 2011;186:4140-6 pubmed publisher
    ..Thus, in addition to gene expression, translational regulation by p38 MAPK could be a novel mechanism that contributes to the overall production of cytokine by NKT cells. ..
  48. Tung C, Jian Y, Chen J, Wang T, Chen W, Zheng H, et al. Curcumin downregulates p38 MAPK-dependent X-ray repair cross-complement group 1 (XRCC1) expression to enhance cisplatin-induced cytotoxicity in human lung cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2016;389:657-66 pubmed publisher
    ..Furthermore, transfection with constitutive active MKK6 or HA-p38 MAPK vectors rescued the XRCC1 protein level and also the cell survival suppressed by cisplatin and ..
  49. Robaszkiewicz A, Wiśnik E, Regdon Z, Chmielewska K, Virag L. PARP1 facilitates EP300 recruitment to the promoters of the subset of RBL2-dependent genes. Biochim Biophys Acta Gene Regul Mech. 2017;: pubmed publisher
    ..We conclude that RBL2 may indirectly regulate transcription of some genes by controlling PARP1-mediated EP300 recruitment. ..
  50. Huang H, Li Y, Chung M. Activin A induction of erythroid differentiation through MKK6-p38alpha/p38beta pathway is inhibited by follistatin. J Cell Physiol. 2010;223:687-94 pubmed publisher
    ..Activin A-induced phosphorylation of MKK6 and p38 was also inhibited by follistatin...
  51. Hong S, Lim S, Li A, Lee C, Lee Y, Lee E, et al. Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat Immunol. 2007;8:504-13 pubmed
    ..Thus, Smad7 is a critical mediator of TGF-beta signals that block proinflammatory TNF signals. ..
  52. Ebel M, Awe O, Kaplan M, Kansas G. Diverse inflammatory cytokines induce selectin ligand expression on murine CD4 T cells via p38α MAPK. J Immunol. 2015;194:5781-8 pubmed publisher
    ..Constitutively active MKK6, an immediate upstream activator of p38 MAPK, induced selectin ligand expression equivalent to that of cytokines, ..
  53. Zhao C, Huang D, Peng T, Huang M, Xie C, Chen J, et al. Molecular cloning, characterization and function of a germinal center kinase MST4 gene from Litopenaeus vannamei in response to Vibrio alginolyticus challenge in TLR-TRAF6 signaling pathway. Dev Comp Immunol. 2017;73:206-219 pubmed publisher
    ..shrimp, RNAi silencing of LvMST4 with dsRNA had no significant effect on THC but seemed to activate the TRAF6-MKK6-p38 pathway and reduced RB activity. In shrimp challenged with V...
  54. Chen Z, Hutchison M, Cobb M. Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain. J Biol Chem. 1999;274:28803-7 pubmed
    ..These results suggest that TAO proteins lie in stress-sensitive kinase cascades and define a mechanism by which these kinases may organize downstream targets. ..
  55. Witte D, Otterbein H, Förster M, Giehl K, Zeiser R, Lehnert H, et al. Negative regulation of TGF-?1-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b. Sci Rep. 2017;7:17313 pubmed publisher
    ..Smad signalling, we studied here whether Rac1b also impacts TGF-?1-dependent non-Smad signalling such as the MKK6-p38 and MEK-ERK mitogen-activated protein kinase (MAPK) pathways and epithelial-mesenchymal transition (EMT)...
  56. Cong F, Goff S. c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation. Proc Natl Acad Sci U S A. 1999;96:13819-24 pubmed
    ..A C-terminal truncation mutant of c-Abl showed no activity for stimulating p38 and MKK6, while a kinase-deficient c-Abl mutant still retained a residual activity...
  57. Hsu C, Chan D, Greggio E, Saha S, Guillily M, Ferree A, et al. MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. J Neurochem. 2010;112:1593-604 pubmed publisher
    ..Over-expression of LRRK2 and MKK6 increased the steady state levels of each protein beyond that observed with over-expression of either protein alone...
  58. 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
    ..045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets. ..
  59. Wang Q, Li Y, Zhang Z, Fang Y, Li X, Sun Y, et al. Bioinformatics analysis of gene expression profiles of osteoarthritis. Acta Histochem. 2015;117:40-6 pubmed publisher
    ..The MAPK signaling and Wnt signaling pathways were closely associated with OA. The DEGs, such as PTTG1, MAP2K6, PPP3CC and CSNK1E, may be the potential targets for OA diagnosis and treatment. ..
  60. Marampon F, Gravina G, Festuccia C, Popov V, Colapietro E, Sanità P, et al. Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis. J Endocrinol Invest. 2016;39:411-22 pubmed publisher
    ..5 μM) p38-inhibitor or by over/expressing MKK6 p38-upstream activator. Vit...
  61. Kang S, Kim J, Shin D. Inhibition of senescence and promotion of the proliferation of chondrocytes from articular cartilage by CsA and FK506 involves inhibition of p38MAPK. Mech Ageing Dev. 2016;153:7-13 pubmed publisher
    ..The early onset of senescence in chondrocyte harboring MKK6E, which is a constitutively-active form of MKK6 and increases p38MAPK phosphorylation, was blocked by CsA...
  62. Lu Y, Zhao Q, Liu Y, Zhang L, Li D, Zhu Z, et al. Vibration loading promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells via p38 MAPK signaling pathway. J Biomech. 2018;71:67-75 pubmed publisher
    ..p38 and MKK6 genes expression, and p38 phosphorylation were promoted in LMHFV-induced osteogenesis...
  63. Bode J, Ludwig S, Freitas C, Schaper F, Ruhl M, Melmed S, et al. The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. Biol Chem. 2001;382:1447-53 pubmed
    ..We analyzed the role of MKK6/p38MAPK for IL-6 signal transduction and transcriptional activation of the suppressor of cytokine signaling (SOCS) ..
  64. Sakurai M, Shiromoto Y, Ota H, Song C, Kossenkov A, Wickramasinghe J, et al. ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay. Nat Struct Mol Biol. 2017;24:534-543 pubmed publisher
    ..Here, we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and its export from the nucleus...
  65. Cuenda A, Alonso G, Morrice N, Jones M, Meier R, Cohen P, et al. Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. EMBO J. 1996;15:4156-64 pubmed
    ..protein kinase kinases (SAPKKs) have been identified in several mammalian cells, termed SAPKK2 and SAPKK3, which activate the MAP kinase family member RK/p38 but not JNK/SAPK in vitro...
  66. Li L, Hu J, He T, Zhang Q, Yang X, Lan X, et al. P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury. Sci Rep. 2015;5:8895 pubmed publisher
    ..In contrast, MKK6 (Glu), which constitutively activated p38/MAPK, resulted in microtubule depolymerisation and, subsequently, ..
  67. Liu Z, Lv Y, Zhang Y, Liu F, Zhu L, Pan S, et al. Matrine-Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species-Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling. J Am Heart Assoc. 2017;6: pubmed publisher
    ..protein kinase (MAPK) inhibitor, and small interference RNAs against p38 MAPK kinases MAPK kinase kinase (MKK)3 and MKK6 were administrated...
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    ..These results demonstrated that the association between the kinase domain of TAK1 and the C-terminal TAB1 triggered the phosphorylation-dependent TAK1 activation mechanism. ..
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    ..Overall, our findings point to Mxi2 as a unique member of the p38 family that may have an unprecedented role in the regulation of the functions of ERK mitogen-activated protein kinases. ..
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    ..A GSEA suggested that the transforming growth factor ?, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response. ..
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    ..This activation of ASK-1 is followed by activation of the mitogen-activated kinase kinases MKK3/MKK6 and MKK4/MMK7 and subsequently p38 and JNK MAP kinases...
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    ..Based on phenotypic defects of single-, double- and triple-deletion mutants, Mkk4, Mkk5 and Mkk6 played collaborative or independent roles in sustaining radial growth on various media, conidiation capacity, ..
  74. Kojima H, Sasaki T, Ishitani T, Iemura S, Zhao H, Kaneko S, et al. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci U S A. 2005;102:4524-9 pubmed
    ..Together, these results indicate that STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases, specifically in the YXXQ motif-derived pathway. ..
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    ..We transduced melanoma cells with adenovirus harboring the expression cassette for constitutive active form of MKK6, an upstream MAPKK for p38 MAPK...
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    ..First, the inflammatory signal-induced MKK6-p38MAPK cascade activates a monocyte differentiation program in human granulocyte colony-stimulating factor-..
  78. Witte D, Bartscht T, Kaufmann R, Pries R, Settmacher U, Lehnert H, et al. TGF-?1-induced cell migration in pancreatic carcinoma cells is RAC1 and NOX4-dependent and requires RAC1 and NOX4-dependent activation of p38 MAPK. Oncol Rep. 2017;38:3693-3701 pubmed publisher
    ..random cell migration, while ectopic expression of a kinase-active version of the p38 activating kinase MKK6 was able to partially rescue the decline in migration after RAC1 inhibition...
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    ..Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38. ..
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    ..We show that conditional induction of a dominant active form of MAPK kinase 6 (d.a.MKK6), a direct upstream kinase of p38, in LCs efficiently induces the up-regulation of costimulatory molecules and ..
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    ..and the cells' proliferation ability was analyzed through MTT; real-time PCR detected the change of MLK3/MKK6/p38MAPK/MSK1/ATF1 on mRNA, and the difference of protein expression of MKK6/p38MAPK were detected through the ..
  83. Weijman J, Kumar A, Jamieson S, King C, Caradoc Davies T, Ledgerwood E, et al. Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1. Proc Natl Acad Sci U S A. 2017;114:E2096-E2105 pubmed publisher
    ..compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation...
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    ..promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively...
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    ..Mechanistic studies in vitro indicate that specific cadherins and immunoglobulin superfamily proteins exert some of their effects in an interdependent fashion by signaling from a multiprotein complex found at sites of cell-cell contact. ..
  86. Ding N, Xiao H, Xu L, She S. [Effect of mitogen-activated protein kinase kinase 6-p38 alpha signal pathway on receptor for advanced glycation end-product expression in alveolar epithelial cells induced by mechanical stretch]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2009;21:597-600 pubmed
    To investigate the role of mitogen-activated protein kinase kinase 6 (MKK6) p38 alpha in mechanical stretch induced receptor for advanced glycation end-product (RAGE) expression in alveolar epithelial cells (A549)...
  87. Shang F, Xia Q, Liu W, Xia L, Qian B, You L, et al. miR-434-3p and DNA hypomethylation co-regulate eIF5A1 to increase AChRs and to improve plasticity in SCT rat skeletal muscle. Sci Rep. 2016;6:22884 pubmed publisher
    ..Finally, HRM and MeDIP-PCR analyses revealed that DNA demethylation also up-regulated eIF5A1 after SCT. Consequently, miR-434-3p/eIF5A1 in muscle is a promising potential biotherapy for SCI repair. ..
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    ..using acetyl-coenzyme A (CoA) to modify the critical serine and threonine residues in the activation loop of MAPKK6 and thereby blocking phosphorylation...
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    ..MEKK4 phosphorylates and activates MKK4/MKK7 and MKK3/MKK6 leading to the activation of JNK and p38, respectively...
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    ..The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus...