| 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]
Publication Abstract from PubMed
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family, which includes JNK1-JNK3. Interestingly, JNK1 and JNK2 show opposing functions, with JNK2 activity favoring cell survival and JNK1 stimulating apoptosis. Isoform-selective small molecule inhibitors of JNK1 or JNK2 would be useful as pharmacological probes but have been difficult to develop due to the similarity of their ATP binding pockets. Here, we describe the discovery of a covalent inhibitor YL5084, the first such inhibitor that displays selectivity for JNK2 over JNK1. We demonstrated that YL5084 forms a covalent bond with Cys116 of JNK2, exhibits a 20-fold higher K(inact)/K(I) compared to that of JNK1, and engages JNK2 in cells. However, YL5084 exhibited JNK2-independent antiproliferative effects in multiple myeloma cells, suggesting the existence of additional targets relevant in this context. Thus, although not fully optimized, YL5084 represents a useful chemical starting point for the future development of JNK2-selective chemical probes.
Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1.,Lu W, Liu Y, Gao Y, Geng Q, Gurbani D, Li L, Ficarro SB, Meyer CJ, Sinha D, You I, Tse J, He Z, Ji W, Che J, Kim AY, Yu T, Wen K, Anderson KC, Marto JA, Westover KD, Zhang T, Gray NS J Med Chem. 2023 Mar 9;66(5):3356-3371. doi: 10.1021/acs.jmedchem.2c01834. Epub , 2023 Feb 24. PMID:36826833[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
- ↑ Lu W, Liu Y, Gao Y, Geng Q, Gurbani D, Li L, Ficarro SB, Meyer CJ, Sinha D, You I, Tse J, He Z, Ji W, Che J, Kim AY, Yu T, Wen K, Anderson KC, Marto JA, Westover KD, Zhang T, Gray NS. Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1. J Med Chem. 2023 Mar 9;66(5):3356-3371. PMID:36826833 doi:10.1021/acs.jmedchem.2c01834
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