| Structural highlights
Function
[MK09_HUMAN] Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons.[1] [2] [3] [4] [5] [6] MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.[7] [8] [9] [10] [11] [12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
JNK2 and p38alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38alpha to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential.
X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors.,Kuglstatter A, Ghate M, Tsing S, Villasenor AG, Shaw D, Barnett JW, Browner MF Bioorg Med Chem Lett. 2010 Sep 1;20(17):5217-20. Epub 2010 Jul 23. PMID:20655210[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ De Graeve F, Bahr A, Sabapathy KT, Hauss C, Wagner EF, Kedinger C, Chatton B. Role of the ATFa/JNK2 complex in Jun activation. Oncogene. 1999 Jun 10;18(23):3491-500. PMID:10376527 doi:http://dx.doi.org/10.1038/sj.onc.1202723
- ↑ Mayer C, Bierhoff H, Grummt I. The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes Dev. 2005 Apr 15;19(8):933-41. Epub 2005 Apr 1. PMID:15805466 doi:http://dx.doi.org/10.1101/gad.333205
- ↑ Oleinik NV, Krupenko NI, Krupenko SA. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene. 2007 Nov 8;26(51):7222-30. Epub 2007 May 21. PMID:17525747 doi:http://dx.doi.org/10.1038/sj.onc.1210526
- ↑ Hu D, Bi X, Fang W, Han A, Yang W. GSK3beta is involved in JNK2-mediated beta-catenin inhibition. PLoS One. 2009 Aug 13;4(8):e6640. doi: 10.1371/journal.pone.0006640. PMID:19675674 doi:http://dx.doi.org/10.1371/journal.pone.0006640
- ↑ Samak G, Suzuki T, Bhargava A, Rao RK. c-Jun NH2-terminal kinase-2 mediates osmotic stress-induced tight junction disruption in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2010 Sep;299(3):G572-84. doi:, 10.1152/ajpgi.00265.2010. Epub 2010 Jul 1. PMID:20595622 doi:http://dx.doi.org/10.1152/ajpgi.00265.2010
- ↑ Tomlinson V, Gudmundsdottir K, Luong P, Leung KY, Knebel A, Basu S. JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis. Cell Death Dis. 2010;1:e29. doi: 10.1038/cddis.2010.7. PMID:21364637 doi:10.1038/cddis.2010.7
- ↑ De Graeve F, Bahr A, Sabapathy KT, Hauss C, Wagner EF, Kedinger C, Chatton B. Role of the ATFa/JNK2 complex in Jun activation. Oncogene. 1999 Jun 10;18(23):3491-500. PMID:10376527 doi:http://dx.doi.org/10.1038/sj.onc.1202723
- ↑ Mayer C, Bierhoff H, Grummt I. The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes Dev. 2005 Apr 15;19(8):933-41. Epub 2005 Apr 1. PMID:15805466 doi:http://dx.doi.org/10.1101/gad.333205
- ↑ Oleinik NV, Krupenko NI, Krupenko SA. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene. 2007 Nov 8;26(51):7222-30. Epub 2007 May 21. PMID:17525747 doi:http://dx.doi.org/10.1038/sj.onc.1210526
- ↑ Hu D, Bi X, Fang W, Han A, Yang W. GSK3beta is involved in JNK2-mediated beta-catenin inhibition. PLoS One. 2009 Aug 13;4(8):e6640. doi: 10.1371/journal.pone.0006640. PMID:19675674 doi:http://dx.doi.org/10.1371/journal.pone.0006640
- ↑ Samak G, Suzuki T, Bhargava A, Rao RK. c-Jun NH2-terminal kinase-2 mediates osmotic stress-induced tight junction disruption in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2010 Sep;299(3):G572-84. doi:, 10.1152/ajpgi.00265.2010. Epub 2010 Jul 1. PMID:20595622 doi:http://dx.doi.org/10.1152/ajpgi.00265.2010
- ↑ Tomlinson V, Gudmundsdottir K, Luong P, Leung KY, Knebel A, Basu S. JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis. Cell Death Dis. 2010;1:e29. doi: 10.1038/cddis.2010.7. PMID:21364637 doi:10.1038/cddis.2010.7
- ↑ Kuglstatter A, Ghate M, Tsing S, Villasenor AG, Shaw D, Barnett JW, Browner MF. X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5217-20. Epub 2010 Jul 23. PMID:20655210 doi:10.1016/j.bmcl.2010.06.157
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