mitogen activated protein kinase 10


Summary: A c-jun amino-terminal kinase that is found predominantly within NEURONS of the BRAIN, suggesting a role in stress-induced neuronal APOPTOSIS. Several isoforms of the protein with molecular sizes of 47 kDa and 52 kDa exist due to multiple ALTERNATIVE SPLICING.

Top Publications

  1. Yang D, Kuan C, Whitmarsh A, Rincon M, Zheng T, Davis R, et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature. 1997;389:865-70 pubmed
    ..These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity. ..
  2. Resnick L, Fennell M. Targeting JNK3 for the treatment of neurodegenerative disorders. Drug Discov Today. 2004;9:932-9 pubmed
    ..Because of the involvement of JNK3 in neuronal diseases, the inhibition of this enzyme is an attractive therapeutic target. ..
  3. Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, et al. JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol. 1999;19:7539-48 pubmed
    ..These results suggest that JSAP1 functions as a scaffold protein in the JNK3 cascade. We also discuss a scaffolding role for JSAP1 in the JNK1 and JNK2 cascades. ..
  4. Davis R. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239-52 pubmed
  5. McDonald P, Chow C, Miller W, Laporte S, Field M, Lin F, et al. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science. 2000;290:1574-7 pubmed
    ..Thus, beta-arrestin 2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a GPCR. ..
  6. Coffey E, Smiciene G, Hongisto V, Cao J, Brecht S, Herdegen T, et al. c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. J Neurosci. 2002;22:4335-45 pubmed
    ..Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity. ..
  7. Mohit A, Martin J, Miller C. p493F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system. Neuron. 1995;14:67-78 pubmed
    ..The p493F12 gene maps to the human chromosome 21q21 region, a region that may be important in the pathogenesis of AD and Down's syndrome. ..
  8. Kuan C, Whitmarsh A, Yang D, Liao G, Schloemer A, Dong C, et al. A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci U S A. 2003;100:15184-9 pubmed
    ..The downstream mechanism of JNK3-mediated apoptosis may include the induction of Bim and Fas and the mitochondrial release of cytochrome c. These results suggest that JNK3 is a potential target for neuroprotection therapies in stroke. ..
  9. Björkblom B, Vainio J, Hongisto V, Herdegen T, Courtney M, Coffey E. All JNKs can kill, but nuclear localization is critical for neuronal death. J Biol Chem. 2008;283:19704-13 pubmed publisher
    ..Thus any one of the three JNKs is capable of mediating apoptosis and inhibition of nuclear JNK is protective. ..

More Information


  1. Martin J, Mohit A, Miller C. Developmental expression in the mouse nervous system of the p493F12 SAP kinase. Brain Res Mol Brain Res. 1996;35:47-57 pubmed
    ..As the amino acid sequence is highly conserved in the human and mouse, the latter may serve as a model for regulation and expression of this kinase. ..
  2. Pei D, Sun Y, Guan Q, Hao Z, Xu T, Zhang G. Postsynaptic density protein 95 antisense oligodeoxynucleotides inhibits the activation of MLK3 and JNK3 via the GluR6.PSD-95.MLK3 signaling module after transient cerebral ischemia in rat hippocampus. Neurosci Lett. 2004;367:71-5 pubmed
    ..These results indicate that PSD-95 plays an important role in the formation of the GluR6.PSD-95.MLK3 signaling module and MLK3 and JNK3 activation in postischemic rat hippocampus. ..
  3. Tian H, Zhang G, Li H, Zhang Q. Antioxidant NAC and AMPA/KA receptor antagonist DNQX inhibited JNK3 activation following global ischemia in rat hippocampus. Neurosci Res. 2003;46:191-7 pubmed
    ..Ketamine and nifedipine had no significant effects on JNK3 activation during reperfusion. Consequently, reactive oxygen species (ROS) and AMPA/KA receptor were closely associated with JNK3 activation following global ischemia. ..
  4. Christopher J, Atkinson F, Bax B, Brown M, Champigny A, Chuang T, et al. 1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3. Bioorg Med Chem Lett. 2009;19:2230-4 pubmed publisher
    ..X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent. ..
  5. Yacoub A, Gupta P, Park M, Rhamani M, Hamed H, Hanna D, et al. Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther. 2008;7:314-29 pubmed publisher
  6. Tian H, Zhang Q, Zhu G, Pei D, Guan Q, Zhang G. Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6.PSD-95.MLK3 signaling module following cerebral ischemia in rat hippocampus. Brain Res. 2005;1061:57-66 pubmed
    ..Consequently, GluR6, one subunit of kainate receptor, plays a critical role in inducing JNK3 activation after ischemic injury. ..
  7. Jayanthi S, McCoy M, Ladenheim B, Cadet J. Methamphetamine causes coordinate regulation of Src, Cas, Crk, and the Jun N-terminal kinase-Jun pathway. Mol Pharmacol. 2002;61:1124-31 pubmed
    ..These values returned to baseline by 1 week after drug treatment. These results are discussed in terms of their support for a possible role of the activation of the JNK/Jun pathway in the pathophysiological effects of METH. ..
  8. Tachibana H, Perrino C, Takaoka H, Davis R, Naga Prasad S, Rockman H. JNK1 is required to preserve cardiac function in the early response to pressure overload. Biochem Biophys Res Commun. 2006;343:1060-6 pubmed
    ..These data suggest that JNK1 plays a protective role in response to pressure overload, preventing the early deterioration in cardiac function following an acute increase in afterload. ..
  9. Szczepankiewicz B, Kosogof C, Nelson L, Liu G, Liu B, Zhao H, et al. Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. J Med Chem. 2006;49:3563-80 pubmed
    ..The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases. ..
  10. Shackelford D, Yeh R. Differential effects of ischemia and reperfusion on c-Jun N-terminal kinase isoform protein and activity. Brain Res Mol Brain Res. 2001;94:178-92 pubmed
    ..However, specific JNK isoform activation may participate in the cell death pathways as increased activity of novel c-Jun (ATF-2) kinase activities was observed in paraplegic animals. ..
  11. Standen C, Brownlees J, Grierson A, Kesavapany S, Lau K, McLoughlin D, et al. Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer's disease amyloid precursor protein by stress-activated protein kinase 1b (Jun N-terminal kinase-3). J Neurochem. 2001;76:316-20 pubmed
    ..This finding provides a molecular framework to link cellular stresses with APP metabolism in both normal and disease states. ..
  12. Yoshida K, Weichselbaum R, Kharbanda S, Kufe D. Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage. Mol Cell Biol. 2000;20:5370-80 pubmed
    ..These findings indicate that activation of SAPK by DNA damage is mediated in part by Lyn and that the Lyn-->MEKK1-->MKK7-->SAPK pathway is functional in the induction of apoptosis by genotoxic agents. ..
  13. Suzuki J, Yamasaki S, Wu J, Koretzky G, Saito T. The actin cloud induced by LFA-1-mediated outside-in signals lowers the threshold for T-cell activation. Blood. 2007;109:168-75 pubmed
    ..The formation of the actin cloud lowers the threshold for subsequent T-cell activation. Thus, the actin cloud induced by LFA-1 engagement may serve as a possible platform for LFA-1-mediated costimulatory function for T-cell activation. ..
  14. Song X, Gurevich E, Gurevich V. Cone arrestin binding to JNK3 and Mdm2: conformational preference and localization of interaction sites. J Neurochem. 2007;103:1053-62 pubmed
    ..Comparable binding of JNK3 and Mdm2 to four arrestin subtypes allowed us to identify conserved residues likely involved in these interactions. ..
  15. Song X, Raman D, Gurevich E, Vishnivetskiy S, Gurevich V. Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J Biol Chem. 2006;281:21491-9 pubmed
  16. Graczyk P, Khan A, Bhatia G, Palmer V, Medland D, Numata H, et al. The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold. Bioorg Med Chem Lett. 2005;15:4666-70 pubmed
    ..The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurones. ..
  17. Sharma P, Ghoshal N. Exploration of a binding mode of benzothiazol-2-yl acetonitrile pyrimidine core based derivatives as potent c-Jun N-terminal kinase-3 inhibitors and 3D-QSAR analyses. J Chem Inf Model. 2006;46:1763-74 pubmed
    ..The 3D-QSAR model built in this study will provide clear guidelines for a novel inhibitor design based on the benzothiazole derivatives against JNK-3 for the treatment of inflammatory disorders. ..
  18. Johnson G, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911-2 pubmed
    ..The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity. ..
  19. Li C, Xu B, Wang W, Yu X, Zhu J, Yu H, et al. Coactivation of GABA receptors inhibits the JNK3 apoptotic pathway via disassembly of GluR6-PSD-95-MLK3 signaling module in KA-induced seizure. Epilepsia. 2010;51:391-403 pubmed publisher
    ..This provides a new insight into the therapeutic approach to epileptic seizure. ..
  20. Jurewicz A, Matysiak M, Tybor K, Selmaj K. TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3. Brain. 2003;126:1358-70 pubmed
    ..This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis. ..
  21. Kenchappa R, Tep C, Korade Z, Urra S, Bronfman F, Yoon S, et al. p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. J Biol Chem. 2010;285:20358-68 pubmed publisher
  22. Neidhart S, Antonsson B, Gillieron C, Vilbois F, Grenningloh G, Arkinstall S. c-Jun N-terminal kinase-3 (JNK3)/stress-activated protein kinase-beta (SAPKbeta) binds and phosphorylates the neuronal microtubule regulator SCG10. FEBS Lett. 2001;508:259-64 pubmed
    ..Together these observations indicate that activation of JNK/SAPKs provides a pathway for phosphorylation of SCG10 and control of growth cone microtubule formation following neuronal exposure to cellular stresses. ..
  23. de Lemos L, Junyent F, Verdaguer E, Folch J, Romero R, Pallas M, et al. Differences in activation of ERK1/2 and p38 kinase in Jnk3 null mice following KA treatment. J Neurochem. 2010;114:1315-22 pubmed publisher
    ..Therefore, the data indicate that the lack of the JNK3 protein modulates other MAPKs and these changes could also have a pivotal role in neuroprotection. ..
  24. Bruckner S, Tammariello S, Kuan C, Flavell R, Rakic P, Estus S. JNK3 contributes to c-Jun activation and apoptosis but not oxidative stress in nerve growth factor-deprived sympathetic neurons. J Neurochem. 2001;78:298-303 pubmed
    ..Overall, these results indicate that JNK3 plays a critical role in activation of c-Jun and apoptosis in a classic model of cell-autonomous programmed neuron death. ..
  25. Yao K, Cho Y, Bode A, Vummenthala A, Park J, Liu K, et al. A selective small-molecule inhibitor of c-Jun N-terminal kinase 1. FEBS Lett. 2009;583:2208-12 pubmed publisher
    ..These results demonstrate that AV-7 is an isoform selective small-molecule inhibitor of JNK1 activity, which might be developed as a therapeutic against diabetes. ..
  26. Yoshida S, Harada H, Nagai H, Fukino K, Teramoto A, Emi M. Head-to-head juxtaposition of Fas-associated phosphatase-1 (FAP-1) and c-Jun NH2-terminal kinase 3 (JNK3) genes: genomic structure and seven polymorphisms of the FAP-1 gene. J Hum Genet. 2002;47:614-9 pubmed
    ..Seven polymorphisms were identified within functional domains or the putative promoter region, including two with amino acid substitutions, Leu1419Pro and Ile1522Met. ..
  27. Shoichet S, Duprez L, Hagens O, Waetzig V, Menzel C, Herdegen T, et al. Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy. Hum Genet. 2006;118:559-67 pubmed
    ..These interactions are likely affected by a truncated JNK3 protein, and thereby provide an explanation for the link between alterations in MAP kinase signal transduction and brain disorders. ..
  28. Masui K, Yamada E, Shimokawara T, Mishima K, Enomoto Y, Nakajima H, et al. Expression of c-Jun N-terminal kinases after axotomy in the dorsal motor nucleus of the vagus nerve and the hypoglossal nucleus. Acta Neuropathol. 2002;104:123-9 pubmed
  29. Park S, Oh E, Yoo M, Lee S. Involvement of DNA-dependent protein kinase in regulation of stress-induced JNK activation. DNA Cell Biol. 2001;20:637-45 pubmed
    ..Together, our results suggest that DNA damage induces physical interaction between DNA-PK and JNK, which may in turn negatively affect JNK activity through JNK phosphorylation by DNA-PK. ..
  30. Zhao J, Pei D, Zhang Q, Zhang G. Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. Cell Signal. 2007;19:831-43 pubmed
    ..Thus, Cdc42 may be a potential therapeutic target in ischemic brain injury. ..
  31. Lee J, Park J, Lee Y, Lee S, Han P. Distinct localization of SAPK isoforms in neurons of adult mouse brain implies multiple signaling modes of SAPK pathway. Brain Res Mol Brain Res. 1999;70:116-24 pubmed
    ..In addition, differential regional and subcellular localizations of SAPK isoforms allow us to speculate multiple signaling modes for SAPK activation in brain. ..
  32. Pirianov G, Brywe K, Mallard C, Edwards A, Flavell R, Hagberg H, et al. Deletion of the c-Jun N-terminal kinase 3 gene protects neonatal mice against cerebral hypoxic-ischaemic injury. J Cereb Blood Flow Metab. 2007;27:1022-32 pubmed
    ..These findings implicate JNK3 involvement in neural cell loss resulting from cerebral HII in the developing brain. ..
  33. Sherrin T, Blank T, Hippel C, Rayner M, Davis R, Todorovic C. Hippocampal c-Jun-N-terminal kinases serve as negative regulators of associative learning. J Neurosci. 2010;30:13348-61 pubmed publisher
    ..Together, these results support the possibility that hippocampal JNKs serve as a critical molecular regulator in the formation of contextual fear. ..
  34. Yan F, Wang X, Liu Z, Pan C, Yuan S, Ma Q. JNK1, JNK2, and JNK3 are involved in P-glycoprotein-mediated multidrug resistance of hepatocellular carcinoma cells. Hepatobiliary Pancreat Dis Int. 2010;9:287-95 pubmed
    ..We found that JNK1, JNK2, and JNK3 activities were negatively correlated with the degree of MDR in HCC cells. This study suggests that JNK1, JNK2, and JNK3 activities are negatively correlated with the degree of MDR in HCC cells. ..
  35. Zhang Q, Wang X, Han D, Yin X, Zhang G, Xu T. Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: a protective mechanism against ischemic brain injury. J Neurochem. 2006;98:1886-98 pubmed
  36. Shen Y, Luche R, Wei B, Gordon M, Diltz C, Tonks N. Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1. Proc Natl Acad Sci U S A. 2001;98:13613-8 pubmed
  37. Sadler K. Attention, neurons, this CDK could save your life!. Trends Cell Biol. 2002;12:214 pubmed
  38. Choi J, Park S, Joo C. Hepatocyte growth factor induces proliferation of lens epithelial cells through activation of ERK1/2 and JNK/SAPK. Invest Ophthalmol Vis Sci. 2004;45:2696-704 pubmed
  39. Pan J, Zhang Q, Zhang G. The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region. Neuroscience. 2005;131:147-59 pubmed
    ..Thus, JNK signaling may eventually emerge as a prime target for novel therapeutic approaches to treatment of ischemic stroke, and K252a may serve as a potential and important neuroprotectant in therapeutic aspect in ischemic stroke. ..
  40. Dong Z, Zhou L, Del Villar K, Ghanevati M, Tashjian V, Miller C. JIP1 regulates neuronal apoptosis in response to stress. Brain Res Mol Brain Res. 2005;134:282-93 pubmed
    ..Thus, under certain stress conditions, down-regulation of JIP1 expression makes neurons more susceptible to apoptosis, suggesting JIP may serve as an anti-apoptosis factor. ..
  41. Rochfort S, Towerzey L, Carroll A, King G, Michael A, Pierens G, et al. Latifolians A and B, novel JNK3 kinase inhibitors from the Papua New Guinean plant Gnetum latifolium. J Nat Prod. 2005;68:1080-2 pubmed
    ..The planar structures were determined through detailed 2D NMR analysis. The relative configurations were assigned after examination of the ROESY data and through detailed molecular modeling studies...
  42. Ying J, Li H, Cui Y, Wong A, Langford C, Tao Q. Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter. Leukemia. 2006;20:1173-5 pubmed
  43. Li T, Han D, Chen J, Yu X, Zhang G. Neuroprotection against ischemic brain injury by knockdown of hematopietic progenitor kinase 1 expression. Neuroreport. 2008;19:647-51 pubmed publisher
    ..These results indicate that knockdown of HPK1 expression provides neuroprotection through downregulation activation of the MLK3-MKK7-JNK3 pathway following cerebral ischemia in the rat hippocampus CA1 subfield. ..
  44. Fricker M, LoGrasso P, Ellis S, Wilkie N, Hunt P, Pollack S. Substituting c-Jun N-terminal kinase-3 (JNK3) ATP-binding site amino acid residues with their p38 counterparts affects binding of JNK- and p38-selective inhibitors. Arch Biochem Biophys. 2005;438:195-205 pubmed
    ..Conservative mutations of the Asn-152 and Gln-155 residues inactivated the JNK3 enzyme, possibly interfering with protein folding in a critical hinge region of the protein. ..
  45. Mielke K. Growth-arrest-dependent expression and phosphorylation of p27kip at serine10 is mediated by the JNK pathway in C6 glioma cells. Mol Cell Neurosci. 2008;38:301-11 pubmed publisher
  46. Qi S, Liu Y, Wang W, Wang M, Zhang G. Neuroprotection of ethanol against cerebral ischemia/reperfusion induced brain injury through GABA receptor activation. Brain Res. 2009;1276:151-8 pubmed publisher
    ..The results show a novel potential mechanism underlying ethanol protective effects. ..
  47. Park B, Ham Y, Jeong H, Cho S, Je Y, Yoo K, et al. Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP. Biochem Biophys Res Commun. 2007;361:994-9 pubmed
    ..These results suggest that JNK3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between Smac and XIAP. ..
  48. Abdelli S, Puyal J, Bielmann C, Buchillier V, Abderrahmani A, Clarke P, et al. JNK3 is abundant in insulin-secreting cells and protects against cytokine-induced apoptosis. Diabetologia. 2009;52:1871-80 pubmed publisher
  49. Li Q, Tep C, Yune T, Zhou X, Uchida T, Lu K, et al. Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. J Neurosci. 2007;27:8395-404 pubmed
    ..This report thus unveils a mechanism by which cytochrome c release is under the opposite control of JNK3 and Pin1, regulators for which the activities are intricately coupled. ..
  50. Ham Y, Lim J, Lee S. Distinct roles for JNK1 and JNK3 during TNF-alpha- or etoposide-induced apoptosis in HeLa cells. Mol Cells. 2009;28:509-13 pubmed publisher
    ..These results suggest that the anti-apoptotic mechanism of JNK3 in TNF-alpha-induced apoptosis originates before the apoptotic machinery is triggered. ..
  51. Hu X, Flaws J, Sipes I, Hoyer P. Activation of mitogen-activated protein kinases and AP-1 transcription factor in ovotoxicity induced by 4-vinylcyclohexene diepoxide in rats. Biol Reprod. 2002;67:718-24 pubmed
    ..Taken together, these data provide evidence that accelerated atretic signals induced by VCD is associated with MAPK/AP-1 signaling pathways and phosphorylation of c-Jun plays a significant role in transmitting the apoptotic signals. ..
  52. Shaikh A, Ismael M, Del Carpio C, Tsuboi H, Koyama M, Endou A, et al. Three-dimensional quantitative structure-activity relationship (3 D-QSAR) and docking studies on (benzothiazole-2-yl) acetonitrile derivatives as c-Jun N-terminal kinase-3 (JNK3) inhibitors. Bioorg Med Chem Lett. 2006;16:5917-25 pubmed
    ..The results of 3D-QSAR and docking studies validate each other and hence, the combination of both methodologies provides a powerful tool directed to the design of novel and selective JNK3 inhibitors. ..
  53. Carboni L, Carletti R, Tacconi S, Corti C, Ferraguti F. Differential expression of SAPK isoforms in the rat brain. An in situ hybridisation study in the adult rat brain and during post-natal development. Brain Res Mol Brain Res. 1998;60:57-68 pubmed
    ..The distinct distribution patterns of SAPK isoforms in the adult rat brain support the hypothesis that separate functions are performed by the products of the three SAPK genes. ..