| Structural highlights
Function
MK08_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 MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH.[1] [2] [3] [4] [5] [6] [7] [8] JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.[9] [10] [11] [12] [13] [14] [15] [16]
Publication Abstract from PubMed
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.,Gong L, Han X, Silva T, Tan YC, Goyal B, Tivitmahaisoon P, Trejo A, Palmer W, Hogg H, Jahagir A, Alam M, Wagner P, Stein K, Filonova L, Loe B, Makra F, Rotstein D, Rapatova L, Dunn J, Zuo F, Dal Porto J, Wong B, Jin S, Chang A, Tran P, Hsieh G, Niu L, Shao A, Reuter D, Hermann J, Kuglstatter A, Goldstein D Bioorg Med Chem Lett. 2013 Jun 15;23(12):3565-9. doi: 10.1016/j.bmcl.2013.04.029., Epub 2013 Apr 21. PMID:23664880[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282
- ↑ Zhang L, Yang SH, Sharrocks AD. Rev7/MAD2B links c-Jun N-terminal protein kinase pathway signaling to activation of the transcription factor Elk-1. Mol Cell Biol. 2007 Apr;27(8):2861-9. Epub 2007 Feb 12. PMID:17296730 doi:10.1128/MCB.02276-06
- ↑ Murata T, Shinozuka Y, Obata Y, Yokoyama KK. Phosphorylation of two eukaryotic transcription factors, Jun dimerization protein 2 and activation transcription factor 2, in Escherichia coli by Jun N-terminal kinase 1. Anal Biochem. 2008 May 1;376(1):115-21. doi: 10.1016/j.ab.2008.01.038. Epub 2008 , Feb 6. PMID:18307971 doi:10.1016/j.ab.2008.01.038
- ↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
- ↑ Nasrin N, Kaushik VK, Fortier E, Wall D, Pearson KJ, de Cabo R, Bordone L. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One. 2009 Dec 22;4(12):e8414. doi: 10.1371/journal.pone.0008414. PMID:20027304 doi:10.1371/journal.pone.0008414
- ↑ 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
- ↑ Deng H, Zhang J, Yoon T, Song D, Li D, Lin A. Phosphorylation of Bcl-associated death protein (Bad) by erythropoietin-activated c-Jun N-terminal protein kinase 1 contributes to survival of erythropoietin-dependent cells. Int J Biochem Cell Biol. 2011 Mar;43(3):409-15. doi:, 10.1016/j.biocel.2010.11.011. Epub 2010 Nov 21. PMID:21095239 doi:10.1016/j.biocel.2010.11.011
- ↑ Miotto B, Struhl K. JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress. Mol Cell. 2011 Oct 7;44(1):62-71. doi: 10.1016/j.molcel.2011.06.021. PMID:21856198 doi:10.1016/j.molcel.2011.06.021
- ↑ Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282
- ↑ Zhang L, Yang SH, Sharrocks AD. Rev7/MAD2B links c-Jun N-terminal protein kinase pathway signaling to activation of the transcription factor Elk-1. Mol Cell Biol. 2007 Apr;27(8):2861-9. Epub 2007 Feb 12. PMID:17296730 doi:10.1128/MCB.02276-06
- ↑ Murata T, Shinozuka Y, Obata Y, Yokoyama KK. Phosphorylation of two eukaryotic transcription factors, Jun dimerization protein 2 and activation transcription factor 2, in Escherichia coli by Jun N-terminal kinase 1. Anal Biochem. 2008 May 1;376(1):115-21. doi: 10.1016/j.ab.2008.01.038. Epub 2008 , Feb 6. PMID:18307971 doi:10.1016/j.ab.2008.01.038
- ↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
- ↑ Nasrin N, Kaushik VK, Fortier E, Wall D, Pearson KJ, de Cabo R, Bordone L. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One. 2009 Dec 22;4(12):e8414. doi: 10.1371/journal.pone.0008414. PMID:20027304 doi:10.1371/journal.pone.0008414
- ↑ 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
- ↑ Deng H, Zhang J, Yoon T, Song D, Li D, Lin A. Phosphorylation of Bcl-associated death protein (Bad) by erythropoietin-activated c-Jun N-terminal protein kinase 1 contributes to survival of erythropoietin-dependent cells. Int J Biochem Cell Biol. 2011 Mar;43(3):409-15. doi:, 10.1016/j.biocel.2010.11.011. Epub 2010 Nov 21. PMID:21095239 doi:10.1016/j.biocel.2010.11.011
- ↑ Miotto B, Struhl K. JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress. Mol Cell. 2011 Oct 7;44(1):62-71. doi: 10.1016/j.molcel.2011.06.021. PMID:21856198 doi:10.1016/j.molcel.2011.06.021
- ↑ Gong L, Han X, Silva T, Tan YC, Goyal B, Tivitmahaisoon P, Trejo A, Palmer W, Hogg H, Jahagir A, Alam M, Wagner P, Stein K, Filonova L, Loe B, Makra F, Rotstein D, Rapatova L, Dunn J, Zuo F, Dal Porto J, Wong B, Jin S, Chang A, Tran P, Hsieh G, Niu L, Shao A, Reuter D, Hermann J, Kuglstatter A, Goldstein D. Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties. Bioorg Med Chem Lett. 2013 Jun 15;23(12):3565-9. doi: 10.1016/j.bmcl.2013.04.029., Epub 2013 Apr 21. PMID:23664880 doi:http://dx.doi.org/10.1016/j.bmcl.2013.04.029
|
