map kinase kinase 4


Summary: A mitogen-activated protein kinase kinase with specificity for JNK MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES and the RETINOID X RECEPTORS. It takes part in a SIGNAL TRANSDUCTION pathway that is activated in response to cellular stress.

Top Publications

  1. Warmka J, Solberg E, Zeliadt N, Srinivasan B, Charlson A, Xing C, et al. Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog. Biochem Biophys Res Commun. 2012;424:488-92 pubmed publisher
    ..These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer...
  2. Szuster Ciesielska A, Mizerska Dudka M, Daniluk J, Kandefer Szerszen M. Butein inhibits ethanol-induced activation of liver stellate cells through TGF-?, NF?B, p38, and JNK signaling pathways and inhibition of oxidative stress. J Gastroenterol. 2013;48:222-37 pubmed publisher
  3. Kim G, Nigro P, Fujiwara K, Abe J, Berk B. p62 binding to protein kinase C ? regulates tumor necrosis factor ?-induced apoptotic pathway in endothelial cells. Arterioscler Thromb Vasc Biol. 2012;32:2974-80 pubmed publisher
    ..Our results suggest a novel function of p62 that regulates the activity of PKC? by binding to PKC?, thereby activating the PKC?-JNK-caspase 3 apoptotic pathway in endothelial cells. ..
  4. Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A. 2012;109:5322-7 pubmed publisher
    ..Taken together, our study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death. ..
  5. Svensson C, Part K, Künnis Beres K, Kaldmäe M, Fernaeus S, Land T. Pro-survival effects of JNK and p38 MAPK pathways in LPS-induced activation of BV-2 cells. Biochem Biophys Res Commun. 2011;406:488-92 pubmed publisher
    ..In conclusion, the results of this study demonstrate that both the JNK and p38 MAPK pathways possess anti-apoptotic functions in the microglial cell line BV-2 during LPS-induced activation. ..
  6. Kan Z, Jaiswal B, Stinson J, Janakiraman V, Bhatt D, Stern H, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. 2010;466:869-73 pubmed publisher
    ..Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets. ..
  7. Shan L, Redhu N, Saleh A, Halayko A, Chakir J, Gounni A. Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways. J Immunol. 2010;184:7134-43 pubmed publisher
    ..In addition, it may be inferred that TSLPR is involved in the pathogenesis of allergic asthma through the activation of HASM cells by TSLP. ..
  8. Shlevkov E, Morata G. A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila. Cell Death Differ. 2012;19:451-60 pubmed publisher
    ..Thus, our results indicate that stress-induced apoptosis in Drosophila is dependant on an amplification loop mediated by dp53 and JNK. Furthermore, they also demonstrate a mechanism of mutual activation of proapoptotic genes. ..
  9. Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P, et al. T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J. 2011;30:1742-52 pubmed publisher
    ..These results indicate a novel role for MALT1 proteolytic activity in TCR-induced JNK activation and reveal CYLD cleavage as the underlying mechanism. ..

More Information


  1. Xie C, Chan W, Yu S, Zhao J, Cheng C. Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation. Free Radic Biol Med. 2011;51:1365-75 pubmed publisher
    ..Our findings unveil a novel mechanism of drug action by bufalin in colon cancer cells and open up the possibility of treating colorectal cancer through a ROS-dependent autophagy pathway. ..
  2. Lu Y, Wu D, Wang X, Ward S, Cederbaum A. Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice. Free Radic Biol Med. 2010;49:1406-16 pubmed publisher
  3. Al Gayyar M, Abdelsaid M, Matragoon S, Pillai B, El Remessy A. Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity. Br J Pharmacol. 2011;164:170-80 pubmed publisher
    ..Targeting TXNIP expression is a potential therapeutic target for retinal neurodegenerative disease. ..
  4. Sun G, Irvine K. Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. Dev Biol. 2011;350:139-51 pubmed publisher
    ..Our observations identify Jnk signaling as a modulator of Hippo pathway activity in wing imaginal discs, and implicate Yorkie activation in compensatory cell proliferation and disc regeneration. ..
  5. Park S, Jin M, Kim Y, Kim Y, Lee S. Anti-inflammatory effects of aromatic-turmerone through blocking of NF-?B, JNK, and p38 MAPK signaling pathways in amyloid ?-stimulated microglia. Int Immunopharmacol. 2012;14:13-20 pubmed publisher
    ..These novel findings provide new insights into the development of ar-turmerone as a therapeutic agent for the treatment of neurodegenerative disorders. ..
  6. Dai L, Aye Thu C, Liu X, Xi J, Cheung P. TAK1, more than just innate immunity. IUBMB Life. 2012;64:825-34 pubmed publisher
    ..This review will focus on recent developments and also examine the regulation of TAK1 in response to a diverse range of other stimuli including DNA damage, transforming growth factor-?, Wnt, osmotic stress, and hypoxia. ..
  7. Enomoto M, Igaki T. Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila. EMBO Rep. 2013;14:65-72 pubmed publisher
    ..Our data provide a mechanism to explain how oncogenic mutations regulate tumour microenvironment through cell-cell communication. ..
  8. Yao Y, Chen R, Ying C, Zhang G, Rui T, Tao A. Interleukin-33 attenuates doxorubicin-induced cardiomyocyte apoptosis through suppression of ASK1/JNK signaling pathway. Biochem Biophys Res Commun. 2017;493:1288-1295 pubmed publisher
    ..IL-33 may have therapeutic potential for DOX-induced cardiac injury...
  9. Sharma P, Dwarakanath B, Varshney R. Radiosensitization by 2-deoxy-D-glucose and 6-aminonicotinamide involves activation of redox sensitive ASK1-JNK/p38MAPK signaling in head and neck cancer cells. Free Radic Biol Med. 2012;53:1500-13 pubmed publisher
    ..The present study emphasizes the importance of redox alterations in determining radiosensitivity of tumor cells that may greatly influence the outcome of radiation therapy. ..
  10. Liu R, Xing L, Kong D, Jiang J, Shang L, Hao W. Bisphenol A inhibits proliferation and induces apoptosis in micromass cultures of rat embryonic midbrain cells through the JNK, CREB and p53 signaling pathways. Food Chem Toxicol. 2013;52:76-82 pubmed publisher
    ..Multiple signaling pathways, such as the JNK, CREB and p53-mitochondrial apoptosis pathways, participate in these effects. ..
  11. Wei L, Matsumoto H, Yamaguchi H. Propofol attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production through p38 MAPK and SAPK/JNK in alveolar epithelial cells. J Anesth. 2013;27:366-73 pubmed publisher
    ..These results suggest that propofol may modulate inflammatory response at clinically achievable concentrations in ALI. ..
  12. Nomura J, Busso N, Ives A, Tsujimoto S, Tamura M, So A, et al. Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PLoS ONE. 2013;8:e75527 pubmed publisher
    ..These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes. ..
  13. MacKay C, Carroll E, Ibrahim A, Garg A, Inman G, Hay R, et al. E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. Cancer Res. 2014;74:2246-2257 pubmed publisher
  14. Kaneko K, Ito M, Naoe Y, Lacy Hulbert A, Ikeda K. Integrin ?v in the mechanical response of osteoblast lineage cells. Biochem Biophys Res Commun. 2014;447:352-7 pubmed publisher
    ..Thus, integrin ?v may be integral to a mechanosensing machinery in osteoblastic cells and involved in activation of a Src-JNK-YAP/TAZ pathway in response to mechanical stimulation. ..
  15. Lin S, Hoffmann K, Gao C, Petrulionis M, Herr I, Schemmer P. Melatonin promotes sorafenib-induced apoptosis through synergistic activation of JNK/c-jun pathway in human hepatocellular carcinoma. J Pineal Res. 2017;62: pubmed publisher
  16. Kim S, Ryu M, Han J, Jang Y, Kim J, Lee M, et al. Activation of the HMGB1-RAGE axis upregulates TH expression in dopaminergic neurons via JNK phosphorylation. Biochem Biophys Res Commun. 2017;493:358-364 pubmed publisher
    ..Our results suggest that HMGB1 upregulates TH expression to maintain dopaminergic neuronal function via activating RAGE, which is dependent on JNK phosphorylation. ..
  17. Mozar A, Louvet L, Godin C, Mentaverri R, Brazier M, Kamel S, et al. Indoxyl sulphate inhibits osteoclast differentiation and function. Nephrol Dial Transplant. 2012;27:2176-81 pubmed publisher
    ..Our findings strongly suggest that IS not only inhibits osteoblast function but also has an inhibitory effect on OCL function and thus could affect bone remodelling in CKD patients. ..
  18. Kwon T, Jeong S, Lee H, Lee H, Sohn E, Jung J, et al. Reactive oxygen species-mediated activation of JNK and down-regulation of DAXX are critically involved in penta-O-galloyl-beta-d-glucose-induced apoptosis in chronic myeloid leukemia K562 cells. Biochem Biophys Res Commun. 2012;424:530-7 pubmed publisher
    ..Overall, these findings suggest that ROS-dependent JNK activation and DAXX downregulation are critically involved in PGG-induced apoptosis in K562 cells...
  19. Gowda P, Zhou F, Chadwell L, McEwen D. p53 binding prevents phosphatase-mediated inactivation of diphosphorylated c-Jun N-terminal kinase. J Biol Chem. 2012;287:17554-67 pubmed publisher
  20. Hwang M, Ryu B, Kim S. AW00179 potentiates TRAIL-mediated death of human lung cancer H1299 cells through ROS-JNK-c-Jun-mediated up-regulation of DR5 and down-regulation of anti-apoptotic molecules. Amino Acids. 2012;43:1679-87 pubmed
    ..In conclusion, AW00179 has the potential to sensitize H1299 cells to TRAIL-mediated apoptosis through two distinct mechanisms: ROS-JNK-c-Jun-mediated up-regulation of DR5, and down-regulation of anti-apoptotic molecules. ..
  21. Hsu W, Lee B, Liao T, Hsu Y, Pan T. Monascus-fermented metabolite monascin suppresses inflammation via PPAR-? regulation and JNK inactivation in THP-1 monocytes. Food Chem Toxicol. 2012;50:1178-86 pubmed publisher
    ..Thus, the metabolites from Monascus fermentation may serve as a dietary source of anti-inflammatory agents. ..
  22. 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
    ..The results show how signaling outcomes can be affected by the relative expression of scaffolding proteins and components of signaling cascades that they assemble. ..
  23. Villicaña C, Cruz G, Zurita M. The genetic depletion or the triptolide inhibition of TFIIH in p53-deficient cells induces a JNK-dependent cell death in Drosophila. J Cell Sci. 2013;126:2502-15 pubmed publisher
  24. Jakobsen H, Bojer M, Marinus M, Xu T, Struve C, Krogfelt K, et al. The alkaloid compound harmane increases the lifespan of Caenorhabditis elegans during bacterial infection, by modulating the nematode's innate immune response. PLoS ONE. 2013;8:e60519 pubmed publisher
    ..elegans has a high degree of evolutionary conservation, drugs such as Harmane could also be possible alternatives to classic antibiotics. The C. elegans model could prove to be useful for selection and development of such drugs. ..
  25. Tang Y, Liu C, Chang H, Juan C, Kuo Y, Kao C, et al. Endothelin-1 stimulates resistin gene expression. Endocrinology. 2014;155:854-64 pubmed publisher
    ..In vivo observations that ET-1 increased resistin mRNA and protein levels in sc and epididymal adipose tissues support the in vitro findings. ..
  26. Bartok B, Hammaker D, Firestein G. Phosphoinositide 3-kinase ? regulates migration and invasion of synoviocytes in rheumatoid arthritis. J Immunol. 2014;192:2063-70 pubmed publisher
    ..These observations, together with previous findings that PI3K? regulates FLS growth and survival, suggest that PI3K? inhibition could be chondroprotective in RA by modulating synoviocyte growth, migration, and invasion. ..
  27. Zhang T, Fu J, Geng Z, Yang J, Sun X. The neuroprotective effect of losartan through inhibiting AT1/ASK1/MKK4/JNK3 pathway following cerebral I/R in rat hippocampal CA1 region. CNS Neurosci Ther. 2012;18:981-7 pubmed publisher
    ..used to detect the interactions between ?-arrestin-2 and AT1/apoptosis signal-regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R...
  28. An J, Mehrhof F, Harms C, Lättig Tünnemann G, Lee S, Endres M, et al. ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis. J Hepatol. 2013;58:297-305 pubmed publisher
    ..The efficacy of TAT-ARC protein transduction in murine AAP hepatotoxicity suggests its therapeutic potential for reversing AAP intoxication also in humans. ..
  29. Anandi V, Ashiq K, Nitheesh K, Lahiri M. Platelet-activating factor promotes motility in breast cancer cells and disrupts non-transformed breast acinar structures. Oncol Rep. 2016;35:179-88 pubmed publisher
    ..Taken together this study signifies a novel role of PAF in inducing transformation of non-tumorigenic cells and the vital role in promotion of breast cancer cell migration. ..
  30. Tam S, Richmond D, Kaminker J, Modrusan Z, Martin McNulty B, Cao T, et al. Death receptors DR6 and TROY regulate brain vascular development. Dev Cell. 2012;22:403-17 pubmed publisher
    ..These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. ..
  31. Wu S, Cao Z, Chang K, Juang J. Intestinal microbial dysbiosis aggravates the progression of Alzheimer's disease in Drosophila. Nat Commun. 2017;8:24 pubmed publisher
    ..Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease. ..
  32. Gelderblom M, Leypoldt F, Lewerenz J, Birkenmayer G, Orozco D, Ludewig P, et al. The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice. J Cereb Blood Flow Metab. 2012;32:835-43 pubmed publisher
    ..Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. ..
  33. Canh Hiep N, Kinohira S, Furuyama K, Taketani S. Depletion of glutamine enhances sodium butyrate-induced erythroid differentiation of K562 cells. J Biochem. 2012;152:509-19 pubmed publisher
  34. Ishida K, Nishizuka S, Chiba T, Ikeda M, Kume K, Endo F, et al. Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers. PLoS ONE. 2012;7:e43236 pubmed publisher
    ..These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers. ..
  35. Mitra S, Srivastava A, Khandelwal S. Tributyltin chloride induced testicular toxicity by JNK and p38 activation, redox imbalance and cell death in sertoli-germ cell co-culture. Toxicology. 2013;314:39-50 pubmed publisher
    ..Tesmin levels were significantly diminished and histopathological studies revealed marked tissue damage. Our data collectively indicates the toxic manifestations of TBTC on the male reproductive system and the mechanisms involved. ..
  36. Lan X, Rai P, Chandel N, Cheng K, Lederman R, Saleem M, et al. Morphine induces albuminuria by compromising podocyte integrity. PLoS ONE. 2013;8:e55748 pubmed publisher
    ..These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes. ..
  37. Huang M, Wang P, Huang J, Zhang X, Wang L, Liu H, et al. [Expression and clinicopathological significance of serine-257/threonine-261 phosphorylated MKK4 in colorectal carcinoma]. Zhonghua Yi Xue Za Zhi. 2013;93:746-50 pubmed
    ..A high-level expression of pMKK4 indicates favorable clinical outcomes, but it is not an independent predictor. ..
  38. Yin F, Jiang T, Cadenas E. Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling. Biochem Soc Trans. 2013;41:101-5 pubmed publisher
  39. Qu C, Li W, Shao Q, Dwyer T, Huang H, Yang T, et al. c-Jun N-terminal kinase 1 (JNK1) is required for coordination of netrin signaling in axon guidance. J Biol Chem. 2013;288:1883-95 pubmed publisher
    ..Knockdown of JNK1 in ovo caused defects in spinal cord commissural axon projection and pathfinding. Our study reveals that JNK1 is important in the coordination of DCC and DSCAM in Netrin-mediated attractive signaling. ..
  40. Rodriguez Blanco J, Martin V, García Santos G, Herrera F, Casado Zapico S, Antolin I, et al. Cooperative action of JNK and AKT/mTOR in 1-methyl-4-phenylpyridinium-induced autophagy of neuronal PC12 cells. J Neurosci Res. 2012;90:1850-60 pubmed publisher
    ..In conclusion, the boost in oxidants from MPP(+) treatment in neuronal PC12 is modulating both survival (AKT/mTOR) and death (JNK) pathways, which are the perpetrators of an autophagic cell death. ..
  41. Lee H, Yi T, Baek K, Kwon A, Hwang H, Qadir A, et al. Tumor necrosis factor-? enhances the transcription of Smad ubiquitination regulatory factor 1 in an activating protein-1- and Runx2-dependent manner. J Cell Physiol. 2013;228:1076-86 pubmed publisher
    ..These results suggest that the JNK/AP-1 and ERK/Runx2 signaling pathways mediate TNF-?-dependent Smurf1 transcription. ..
  42. Xiang J, Chen D, Yang L. Effect of PANDER in ?TC6-cell lipoapoptosis and the protective role of exendin-4. Biochem Biophys Res Commun. 2012;421:701-6 pubmed publisher
    ..Exendin-4 may protect against lipoapoptosis by interfering with the JNK-PANDER pathway. ..
  43. Suzuki H, Matsuoka M. The JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death. Mol Cell Biochem. 2013;372:241-8 pubmed publisher
    ..These data together suggest that the JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death. ..
  44. Tarapore R, Yang Y, Katz J. Restoring KLF5 in esophageal squamous cell cancer cells activates the JNK pathway leading to apoptosis and reduced cell survival. Neoplasia. 2013;15:472-80 pubmed
    ..Thus, restoring KLF5 in ESCC cells promotes apoptosis and decreases cell survival in a JNK-dependent manner, providing a potential therapeutic target for human ESCC. ..
  45. Lee M, Choi S, Ha E, An S, Kim T, Han S, et al. Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-?B. Metabolism. 2012;61:1142-51 pubmed publisher
    ..FGF-21 inhibited palmitate-induced NF-?B activation in HSMMs. The results of the present study suggest that FGF-21 prevents palmitate-induced insulin resistance in HSMMs by inhibiting the activation of stress kinase and NF-?B. ..
  46. Curtis C, Shah S, Chin S, Turashvili G, Rueda O, Dunning M, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346-52 pubmed publisher
    ..Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome. ..
  47. Liu W, Xiao L, Dong C, He M, Pan Y, Xie Y, et al. Long-term low-dose ?-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway. Biochem Biophys Res Commun. 2014;447:388-93 pubmed publisher
    ..These findings suggest that long-term LDR of ?-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway. ..
  48. Genovese G, Carugo A, TEPPER J, Robinson F, Li L, Svelto M, et al. Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. Nature. 2017;542:362-366 pubmed publisher
    ..These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC. ..
  49. Qiu Z, Zhou J, Liu F, Qin X, Dai Y, Ke Y, et al. Deletion of Shp2 in bronchial epithelial cells impairs IL-25 production in vitro, but has minor influence on asthmatic inflammation in vivo. PLoS ONE. 2017;12:e0177334 pubmed publisher
    ..Collectively, our data suggested that deletion of Shp2 impaired IL-25 production in bronchial epithelial cells in vitro, but might yet have minor influence on OVA-induced allergic reaction in vivo. ..
  50. Wang Y, Jiang Z, Kim D, Ueno M, Okimura T, Yamaguchi K, et al. Stimulatory effect of the sulfated polysaccharide ascophyllan on the respiratory burst in RAW264.7 macrophages. Int J Biol Macromol. 2013;52:164-9 pubmed publisher
    ..7 cells. Our findings suggest for the first time that ascophyllan can stimulate macrophages to produce ROS through the activations of NADPH oxidase and JNK MAP kinase. ..
  51. Yang Z, Huang B, Zhang Z, Kang Y, Fu M, Liao W. Effects of IL-1 receptor-associated kinase-4 gene silencing on human osteoblast-like cells. Connect Tissue Res. 2012;53:498-507 pubmed publisher
    ..The results of this study may help improve the understanding of the relationship between IRAK-4 and osteoblast-like cells and the interactions between various cytokines in the periprosthetic inflammatory environment. ..
  52. Funakoshi Tago M, Nagata T, Tago K, Tsukada M, Tanaka K, Nakamura S, et al. Fullerene derivative prevents cellular transformation induced by JAK2 V617F mutant through inhibiting c-Jun N-terminal kinase pathway. Cell Signal. 2012;24:2024-34 pubmed publisher
    ..Taking these findings together, JAK2 V617F mutant-induced JNK signaling pathway is an attractive target for MPN therapy, and pyrrolidinium fullerene derivative is now considered a candidate potent drug for MPNs. ..