| Structural highlights
3v3v is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 1ukh |
| Gene: | MAPK8, JNK1, PRKM8, SAPK1, SAPK1C (HUMAN) |
| Activity: | Mitogen-activated protein kinase, with EC number 2.7.11.24 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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] [JIP1_MOUSE] The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and thus inhibiting the JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response (By similarity).[17] [18]
Publication Abstract from PubMed
c-Jun NH2-terminal kinases (JNKs) and phosphatidylinositol 3-kinase (PI3-K) play critical roles in chronic diseases such as cancer, type II diabetes, and obesity. We describe here the binding of quercetagetin (3,3',4',5,6,7-hydroxyflavone), related flavonoids, and SP600125 to JNK1 and PI3-K by ATP-competitive and immobilized metal ion affinity-based fluorescence polarization assays and measure the effect of quercetagetin on JNK1 and PI3-K activities. Quercetagetin attenuated the phosphorylation of c-Jun and AKT, suppressed AP-1 and NF-kappaB promoter activities, and also reduced cell transformation. It attenuated tumor incidence and reduced tumor volumes in a two-stage skin carcinogenesis mouse model. Our crystallographic structure determination data show that quercetagetin binds to the ATP-binding site of JNK1. Notably, the interaction between Lys55, Asp169, and Glu73 of JNK1 and the catechol moiety of quercetagetin reorients the N-terminal lobe of JNK1, thereby improving compatibility of the ligand with its binding site. The results of a theoretical docking study suggest a binding mode of PI3-K with the hydroxyl groups of the catechol moiety forming hydrogen bonds with the side chains of Asp964 and Asp841 in the p110gamma catalytic subunit. These interactions could contribute to the high inhibitory activity of quercetagetin against PI3-K. Our study suggests the potential use of quercetagetin in the prevention or therapy of cancer and other chronic diseases.
Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin.,Baek S, Kang NJ, Popowicz GM, Arciniega M, Jung SK, Byun S, Song NR, Heo YS, Kim BY, Lee HJ, Holak TA, Augustin M, Bode AM, Huber R, Dong Z, Lee KW J Mol Biol. 2012 Nov 8. pii: S0022-2836(12)00852-2. doi:, 10.1016/j.jmb.2012.10.019. PMID:23142567[19]
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
- ↑ Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997 Aug 1;277(5326):693-6. PMID:9235893
- ↑ Whitmarsh AJ, Kuan CY, Kennedy NJ, Kelkar N, Haydar TF, Mordes JP, Appel M, Rossini AA, Jones SN, Flavell RA, Rakic P, Davis RJ. Requirement of the JIP1 scaffold protein for stress-induced JNK activation. Genes Dev. 2001 Sep 15;15(18):2421-32. PMID:11562351 doi:http://dx.doi.org/10.1101/gad.922801
- ↑ Baek S, Kang NJ, Popowicz GM, Arciniega M, Jung SK, Byun S, Song NR, Heo YS, Kim BY, Lee HJ, Holak TA, Augustin M, Bode AM, Huber R, Dong Z, Lee KW. Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin. J Mol Biol. 2012 Nov 8. pii: S0022-2836(12)00852-2. doi:, 10.1016/j.jmb.2012.10.019. PMID:23142567 doi:http://dx.doi.org/10.1016/j.jmb.2012.10.019
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