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Gene Review

MAPK10  -  mitogen-activated protein kinase 10

Homo sapiens

Synonyms: JNK3, JNK3A, MAP kinase 10, MAP kinase p49 3F12, MAPK 10, ...
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Disease relevance of MAPK10


Psychiatry related information on MAPK10

  • JNK3 is highly expressed and activated in postmortem brains of individuals that suffered from Alzheimer's disease [6].

High impact information on MAPK10

  • One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system [7].
  • 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 [7].
  • Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene [7].
  • Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented [7].
  • We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of beta-arrestin 2 using a yeast two-hybrid screen and by coimmunoprecipitation from mouse brain extracts or cotransfected COS-7 cells [8].

Chemical compound and disease context of MAPK10


Biological context of MAPK10

  • The mitogen-activated kinase activating death domain protein (MADD) that is differentially expressed in neoplastic vs. normal cells (DENN) was identified as a substrate for c-Jun N-terminal kinase 3, the first demonstration of such an activity for this stress-activated kinase that is predominantly expressed in the brain [10].
  • 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 [11].
  • JNK3 alpha 1 is predominantly a neuronal specific MAP kinase that is believed to require, like all MAP kinases, both threonine and tyrosine phosphorylation for maximal enzyme activity [12].
  • Reverse transcription and PCR revealed that JNK3 is endogenously expressed in SCLC cells, but not in either chromaffin or neuronally differentiated PC12 cells [13].
  • In addition, experiments with Jnk(-/-) knockout mice have provided evidence that Jnk3 may be required for apoptosis in the hippocampus in vivo following injection of kainic acid, an excitotoxin, and that Jnk1 and Jnk2 are required for apoptosis in the developing embryonic neural tube [14].

Anatomical context of MAPK10


Associations of MAPK10 with chemical compounds

  • Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3 and triggered the colocalization of beta-arrestin 2 and active JNK3 to intracellular vesicles [8].
  • Here we show that c-Jun N-terminal kinases JNK1, JNK2 and JNK3 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies [18].
  • Our results suggest that activation of pro-apoptotic MLK3/JNK3 cascade can be suppressed through activating anti-apoptotic phosphoinositide 3-kinase/Akt pathway induced by a sublethal ischemic insult, which provides a functional link between Akt and the JNK family of stress-activated kinases in ischemic tolerance [19].
  • Hypertonic stress, elicited by mannitol, also significantly stimulated these same JNKs, although the JNK3 isoforms were most strongly activated [13].
  • Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3 [20].

Physical interactions of MAPK10

  • Using the crystal structure of JNK3 complexed with JNK inhibitors, potential compound-interacting amino acid residues were mutated to the corresponding residues in p38 [11].
  • It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3 [21].

Regulatory relationships of MAPK10

  • In contrast, MKK4-activated JNK3 alpha 1 had no increase in Vmax compared to nonactivated levels and had no phosphorylation on the basis of mass spectrometry [12].
  • Beta-arrestin2 acts as a scaffold to enhance signaling to JNK3 stimulated by overexpression of the MAP3 kinase ASK1 or by agonist activation of the angiotensin 1A receptor [22].

Other interactions of MAPK10

  • JNK2, which localized in the cytoplasm, or JNK3, which was confined in nucleus, remained in the same compartment after UV irradiation [23].
  • The steady-state rate constants kcat, Km(GST-ATF2++), and Km(ATP) for both monophosphorylated and bisphosphorylated JNK3 alpha 1 were within 2-fold between the two enzyme forms, suggesting the addition of tyrosine phosphorylation does not affect the binding of ATF2, ATP, or maximal turnover [12].
  • These data suggest that MKK7 was largely responsible for JNK3 alpha 1 activation and that a single threonine phosphorylation may be all that is needed for JNK3 alpha 1 to be active [12].
  • 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 [24].
  • The data also indicate that the specific step enhanced by beta-arrestin2 involves phosphorylation of JNK3 by the MAP2 kinase MKK4 [22].

Analytical, diagnostic and therapeutic context of MAPK10

  • Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt [19].
  • Thus, JNKs the relevant MAP kinases for the NGF-induced formation and elongation of PC12 cells, and this process is also supported by JNK2 and JNK3 which are commonly considered as pro-apoptotic signal transducers [25].
  • A minor pool of phosphorylated JNK3 increased above the control level after reperfusion in hippocampal but not in neocortical particulate fractions [26].
  • Here, examples are provided of how the combination of NMR SHAPES screening, virtual screening, molecular modeling and X-ray crystallography has led to novel drug scaffolds in several drug discovery programs: JNK3 MAP kinase and the fatty acid binding protein, aP2 [27].


  1. TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3. Jurewicz, A., Matysiak, M., Tybor, K., Selmaj, K. Brain (2003) [Pubmed]
  2. The c-Jun NH2-terminal kinase3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. Yoshida, S., Fukino, K., Harada, H., Nagai, H., Imoto, I., Inazawa, J., Takahashi, H., Teramoto, A., Emi, M. J. Hum. Genet. (2001) [Pubmed]
  3. p493F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system. Mohit, A.A., Martin, J.H., Miller, C.A. Neuron (1995) [Pubmed]
  4. Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: a protective mechanism against ischemic brain injury. Zhang, Q.G., Wang, X.T., Han, D., Yin, X.H., Zhang, G.Y., Xu, T.L. J. Neurochem. (2006) [Pubmed]
  5. Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy. Shoichet, S.A., Duprez, L., Hagens, O., Waetzig, V., Menzel, C., Herdegen, T., Schweiger, S., Dan, B., Vamos, E., Ropers, H.H., Kalscheuer, V.M. Hum. Genet. (2006) [Pubmed]
  6. Targeting JNK3 for the treatment of neurodegenerative disorders. Resnick, L., Fennell, M. Drug Discov. Today (2004) [Pubmed]
  7. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Yang, D.D., Kuan, C.Y., Whitmarsh, A.J., Rincón, M., Zheng, T.S., Davis, R.J., Rakic, P., Flavell, R.A. Nature (1997) [Pubmed]
  8. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. McDonald, P.H., Chow, C.W., Miller, W.E., Laporte, S.A., Field, M.E., Lin, F.T., Davis, R.J., Lefkowitz, R.J. Science (2000) [Pubmed]
  9. Antioxidant N-acetylcysteine inhibits the activation of JNK3 mediated by the GluR6-PSD95-MLK3 signaling module during cerebral ischemia in rat hippocampus. Zhang, Q.G., Tian, H., Li, H.C., Zhang, G.Y. Neurosci. Lett. (2006) [Pubmed]
  10. A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. Zhang, Y., Zhou, L., Miller, C.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  11. 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. Fricker, M., Lograsso, P., Ellis, S., Wilkie, N., Hunt, P., Pollack, S.J. Arch. Biochem. Biophys. (2005) [Pubmed]
  12. Activation of JNK3 alpha 1 requires both MKK4 and MKK7: kinetic characterization of in vitro phosphorylated JNK3 alpha 1. Lisnock, J., Griffin, P., Calaycay, J., Frantz, B., Parsons, J., O'Keefe, S.J., LoGrasso, P. Biochemistry (2000) [Pubmed]
  13. Stress- and cell type-dependent regulation of transfected c-Jun N-terminal kinase and mitogen-activated protein kinase kinase isoforms. Butterfield, L., Zentrich, E., Beekman, A., Heasley, L.E. Biochem. J. (1999) [Pubmed]
  14. c-Jun and the transcriptional control of neuronal apoptosis. Ham, J., Eilers, A., Whitfield, J., Neame, S.J., Shah, B. Biochem. Pharmacol. (2000) [Pubmed]
  15. TRAIL-induced death of human adult oligodendrocytes is mediated by JNK pathway. Jurewicz, A., Matysiak, M., Andrzejak, S., Selmaj, K. Glia (2006) [Pubmed]
  16. Specificity in stress response: epidermal keratinocytes exhibit specialized UV-responsive signal transduction pathways. Adachi, M., Gazel, A., Pintucci, G., Shuck, A., Shifteh, S., Ginsburg, D., Rao, L.S., Kaneko, T., Freedberg, I.M., Tamaki, K., Blumenberg, M. DNA Cell Biol. (2003) [Pubmed]
  17. Cisplatin-induced genes as potential markers for thyroid cancer. Lapouge, G., Millon, R., Muller, D., Abecassis, J., Eber, M., Bergerat, J.P., Klein-Soyer, C. Cell. Mol. Life Sci. (2005) [Pubmed]
  18. Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK). Yoshida, H., Hastie, C.J., McLauchlan, H., Cohen, P., Goedert, M. J. Neurochem. (2004) [Pubmed]
  19. Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. Zhang, Q.G., Han, D., Xu, J., Lv, Q., Wang, R., Yin, X.H., Xu, T.L., Zhang, G.Y. Neuroscience (2006) [Pubmed]
  20. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. Gaillard, P., Jeanclaude-Etter, I., Ardissone, V., Arkinstall, S., Cambet, Y., Camps, M., Chabert, C., Church, D., Cirillo, R., Gretener, D., Halazy, S., Nichols, A., Szyndralewiez, C., Vitte, P.A., Gotteland, J.P. J. Med. Chem. (2005) [Pubmed]
  21. Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2. Willoughby, E.A., Collins, M.K. J. Biol. Chem. (2005) [Pubmed]
  22. Identification of a motif in the carboxyl terminus of beta -arrestin2 responsible for activation of JNK3. Miller, W.E., McDonald, P.H., Cai, S.F., Field, M.E., Davis, R.J., Lefkowitz, R.J. J. Biol. Chem. (2001) [Pubmed]
  23. c-JUN N-terminal kinase-1 (JNK1) but not JNK2 or JNK3 is involved in UV signal transduction in human epidermis. Katagiri, C., Negishi, K., Hibino, T. J. Dermatol. Sci. (2006) [Pubmed]
  24. 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. Yoshida, S., Harada, H., Nagai, H., Fukino, K., Teramoto, A., Emi, M. J. Hum. Genet. (2002) [Pubmed]
  25. c-Jun N-terminal kinases (JNKs) and the cytoskeleton--functions beyond neurodegeneration. Gelderblom, M., Eminel, S., Herdegen, T., Waetzig, V. Int. J. Dev. Neurosci. (2004) [Pubmed]
  26. Modulation of ERK and JNK activity by transient forebrain ischemia in rats. Shackelford, D.A., Yeh, R.Y. J. Neurosci. Res. (2006) [Pubmed]
  27. Leveraging structural approaches: applications of NMR-based screening and X-ray crystallography for inhibitor design. Moore, J., Abdul-Manan, N., Fejzo, J., Jacobs, M., Lepre, C., Peng, J., Xie, X. Journal of synchrotron radiation. (2004) [Pubmed]
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