Mitogen-activated protein kinase 8

NameMitogen-activated protein kinase 8
Synonyms
  • 2.7.11.24
  • c-Jun N-terminal kinase 1
  • JNK-46
  • JNK1
  • MAP kinase 8
  • PRKM8
  • SAPK1
  • SAPK1C
  • Stress-activated protein kinase 1c
  • Stress-activated protein kinase JNK1
Gene NameMAPK8
OrganismHuman
Amino acid sequence
>lcl|BSEQ0007270|Mitogen-activated protein kinase 8
MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRP
FQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYIVMELMDANLCQVIQ
MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSF
MMTPYVVTRYYRAPEVILGMGYKENVDLWSVGCIMGEMVCHKILFPGRDYIDQWNKVIEQ
LGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSK
MLVIDASKRISVDEALQHPYINVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKELIYKEV
MDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAA
GPLGCCR
Number of residues427
Molecular Weight48295.14
Theoretical pI6.89
GO Classification
Functions
  • enzyme binding
  • histone deacetylase binding
  • histone deacetylase regulator activity
  • ATP binding
  • JUN kinase activity
  • protein serine/threonine kinase activity
Processes
  • JNK cascade
  • regulation of histone deacetylation
  • programmed cell death
  • toll-like receptor 3 signaling pathway
  • positive regulation of gene expression
  • rhythmic process
  • toll-like receptor 4 signaling pathway
  • peptidyl-threonine phosphorylation
  • response to stress
  • toll-like receptor 5 signaling pathway
  • apoptotic signaling pathway
  • toll-like receptor 9 signaling pathway
  • toll-like receptor signaling pathway
  • intrinsic apoptotic signaling pathway
  • toll-like receptor TLR1
  • peptidyl-serine phosphorylation
  • toll-like receptor TLR6
  • positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway
  • double-strand break repair
  • innate immune response
  • TRIF-dependent toll-like receptor signaling pathway
  • regulation of circadian rhythm
  • positive regulation of apoptotic process
  • negative regulation of protein binding
  • response to UV
  • Fc-epsilon receptor signaling pathway
  • regulation of protein localization
  • cellular response to mechanical stimulus
  • positive regulation of deacetylase activity
  • MyD88-dependent toll-like receptor signaling pathway
  • apoptotic process
  • positive regulation of protein metabolic process
  • MyD88-independent toll-like receptor signaling pathway
  • negative regulation of apoptotic process
  • regulation of sequence-specific DNA binding transcription factor activity
  • neurotrophin TRK receptor signaling pathway
  • stress-activated MAPK cascade
  • protein phosphorylation
  • JUN phosphorylation
  • toll-like receptor 10 signaling pathway
  • cellular response to lipopolysaccharide
  • positive regulation of cyclase activity
  • DNA repair
  • toll-like receptor 2 signaling pathway
Components
  • cytosol
  • nucleoplasm
  • nucleus
General FunctionProtein serine/threonine kinase activity
Specific FunctionSerine/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. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692).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.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID474901
UniProtKB IDP45983
UniProtKB Entry NameMK08_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0017225|Mitogen-activated protein kinase 8 (MAPK8)
ATGAGCAGAAGCAAGCGTGACAACAATTTTTATAGTGTAGAGATTGGAGATTCTACATTC
ACAGTCCTGAAACGATATCAGAATTTAAAACCTATAGGCTCAGGAGCTCAAGGAATAGTA
TGCGCAGCTTATGATGCCATTCTTGAAAGAAATGTTGCAATCAAGAAGCTAAGCCGACCA
TTTCAGAATCAGACTCATGCCAAGCGGGCCTACAGAGAGCTAGTTCTTATGAAATGTGTT
AATCACAAAAATATAATTGGCCTTTTGAATGTTTTCACACCACAGAAATCCCTAGAAGAA
TTTCAAGATGTTTACATAGTCATGGAGCTCATGGATGCAAATCTTTGCCAAGTGATTCAG
ATGGAGCTAGATCATGAAAGAATGTCCTACCTTCTCTATCAGATGCTGTGTGGAATCAAG
CACCTTCATTCTGCTGGAATTATTCATCGGGACTTAAAGCCCAGTAATATAGTAGTAAAA
TCTGATTGCACTTTGAAGATTCTTGACTTCGGTCTGGCCAGGACTGCAGGAACGAGTTTT
ATGATGACGCCTTATGTAGTGACTCGCTACTACAGAGCACCCGAGGTCATCCTTGGCATG
GGCTACAAGGAAAACGTTGACATTTGGTCAGTTGGGTGCATCATGGGAGAAATGATCAAA
GGTGGTGTTTTGTTCCCAGGTACAGATCATATTGATCAGTGGAATAAAGTTATTGAACAG
CTTGGAACACCATGTCCTGAATTCATGAAGAAACTGCAACCAACAGTAAGGACTTACGTT
GAAAACAGACCTAAATATGCTGGATATAGCTTTGAGAAACTCTTCCCTGATGTCCTTTTC
CCAGCTGACTCAGAACACAACAAACTTAAAGCCAGTCAGGCAAGGGATTTGTTATCCAAA
ATGCTGGTAATAGATGCATCTAAAAGGATCTCTGTAGATGAAGCTCTCCAACACCCGTAC
ATCAATGTCTGGTATGATCCTTCTGAAGCAGAAGCTCCACCACCAAAGATCCCTGACAAG
CAGTTAGATGAAAGGGAACACACAATAGAAGAGTGGAAAGAATTGATATATAAGGAAGTT
ATGGACTTGGAGGAGAGAACCAAGAATGGAGTTATACGGGGGCAGCCCTCTCCTTTAGGT
GCAGCAGTGATCAATGGCTCTCAGCATCCATCATCATCGTCGTCTGTCAATGATGTGTCT
TCAATGTCAACAGATCCGACTTTGGCCTCTGATACAGACAGCAGTCTAGAAGCAGCAGCT
GGGCCTCTGGGCTGCTGTAGATGA
GenBank Gene IDL26318
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:6881
Chromosome Location10
Locus10q11.22
References
  1. Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ: JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025-37. 8137421
  2. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ: Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996 Jun 3;15(11):2760-70. 8654373
  3. Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, Sims SK, Jones MC, Searle S, Scott C, Howe K, Hunt SE, Andrews TD, Gilbert JG, Swarbreck D, Ashurst JL, Taylor A, Battles J, Bird CP, Ainscough R, Almeida JP, Ashwell RI, Ambrose KD, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Bates K, Beasley H, Bray-Allen S, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Cahill P, Camire D, Carter NP, Chapman JC, Clark SY, Clarke G, Clee CM, Clegg S, Corby N, Coulson A, Dhami P, Dutta I, Dunn M, Faulkner L, Frankish A, Frankland JA, Garner P, Garnett J, Gribble S, Griffiths C, Grocock R, Gustafson E, Hammond S, Harley JL, Hart E, Heath PD, Ho TP, Hopkins B, Horne J, Howden PJ, Huckle E, Hynds C, Johnson C, Johnson D, Kana A, Kay M, Kimberley AM, Kershaw JK, Kokkinaki M, Laird GK, Lawlor S, Lee HM, Leongamornlert DA, Laird G, Lloyd C, Lloyd DM, Loveland J, Lovell J, McLaren S, McLay KE, McMurray A, Mashreghi-Mohammadi M, Matthews L, Milne S, Nickerson T, Nguyen M, Overton-Larty E, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter K, Rice CM, Rogosin A, Ross MT, Sarafidou T, Sehra HK, Shownkeen R, Skuce CD, Smith M, Standring L, Sycamore N, Tester J, Thorpe A, Torcasso W, Tracey A, Tromans A, Tsolas J, Wall M, Walsh J, Wang H, Weinstock K, West AP, Willey DL, Whitehead SL, Wilming L, Wray PW, Young L, Chen Y, Lovering RC, Moschonas NK, Siebert R, Fechtel K, Bentley D, Durbin R, Hubbard T, Doucette-Stamm L, Beck S, Smith DR, Rogers J: The DNA sequence and comparative analysis of human chromosome 10. Nature. 2004 May 27;429(6990):375-81. 15164054
  4. Goshima N, Kawamura Y, Fukumoto A, Miura A, Honma R, Satoh R, Wakamatsu A, Yamamoto J, Kimura K, Nishikawa T, Andoh T, Iida Y, Ishikawa K, Ito E, Kagawa N, Kaminaga C, Kanehori K, Kawakami B, Kenmochi K, Kimura R, Kobayashi M, Kuroita T, Kuwayama H, Maruyama Y, Matsuo K, Minami K, Mitsubori M, Mori M, Morishita R, Murase A, Nishikawa A, Nishikawa S, Okamoto T, Sakagami N, Sakamoto Y, Sasaki Y, Seki T, Sono S, Sugiyama A, Sumiya T, Takayama T, Takayama Y, Takeda H, Togashi T, Yahata K, Yamada H, Yanagisawa Y, Endo Y, Imamoto F, Kisu Y, Tanaka S, Isogai T, Imai J, Watanabe S, Nomura N: Human protein factory for converting the transcriptome into an in vitro-expressed proteome,. Nat Methods. 2008 Dec;5(12):1011-7. 19054851
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  6. Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ: Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682-5. 7839144
  7. Fleming Y, Armstrong CG, Morrice N, Paterson A, Goedert M, Cohen P: Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Biochem J. 2000 Nov 15;352 Pt 1:145-54. 11062067
  8. Kurokawa M, Mitani K, Yamagata T, Takahashi T, Izutsu K, Ogawa S, Moriguchi T, Nishida E, Yazaki Y, Hirai H: The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. EMBO J. 2000 Jun 15;19(12):2958-68. 10856240
  9. Chang NS, Doherty J, Ensign A: JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J Biol Chem. 2003 Mar 14;278(11):9195-202. Epub 2003 Jan 6. 12514174
  10. Jagadish N, Rana R, Selvi R, Mishra D, Garg M, Yadav S, Herr JC, Okumura K, Hasegawa A, Koyama K, Suri A: Characterization of a novel human sperm-associated antigen 9 (SPAG9) having structural homology with c-Jun N-terminal kinase-interacting protein. Biochem J. 2005 Jul 1;389(Pt 1):73-82. 15693750
  11. 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. 16581800
  12. Yao K, Cho YY, Bergen HR 3rd, Madden BJ, Choi BY, Ma WY, Bode AM, Dong Z: Nuclear factor of activated T3 is a negative regulator of Ras-JNK1/2-AP-1 induced cell transformation. Cancer Res. 2007 Sep 15;67(18):8725-35. 17875713
  13. Zihni C, Mitsopoulos C, Tavares IA, Baum B, Ridley AJ, Morris JD: Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis. JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing. J Biol Chem. 2007 Mar 2;282(9):6484-93. Epub 2006 Dec 11. 17158878
  14. 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. 17296730
  15. 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. 18307971
  16. 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. 18570871
  17. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M: Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008 Aug 8;31(3):438-48. doi: 10.1016/j.molcel.2008.07.007. 18691976
  18. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. 18669648
  19. Zheng B, Matoba Y, Kumagai T, Katagiri C, Hibino T, Sugiyama M: Crystal structure of SCCA1 and insight about the interaction with JNK1. Biochem Biophys Res Commun. 2009 Feb 27;380(1):143-7. doi: 10.1016/j.bbrc.2009.01.057. Epub 2009 Jan 21. 19166818
  20. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H: Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics. 2009 Jul;8(7):1751-64. doi: 10.1074/mcp.M800588-MCP200. Epub 2009 Apr 15. 19369195
  21. 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. 20027304
  22. 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. 21364637
  23. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  24. Park JE, Lee JA, Park SG, Lee DH, Kim SJ, Kim HJ, Uchida C, Uchida T, Park BC, Cho S: A critical step for JNK activation: isomerization by the prolyl isomerase Pin1. Cell Death Differ. 2012 Jan;19(1):153-61. doi: 10.1038/cdd.2011.82. Epub 2011 Jun 10. 21660049
  25. Yoshitane H, Honma S, Imamura K, Nakajima H, Nishide SY, Ono D, Kiyota H, Shinozaki N, Matsuki H, Wada N, Doi H, Hamada T, Honma K, Fukada Y: JNK regulates the photic response of the mammalian circadian clock. EMBO Rep. 2012 May 1;13(5):455-61. doi: 10.1038/embor.2012.37. 22441692
  26. 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. 21095239
  27. Wang J, Tang R, Lv M, Wang Q, Zhang X, Guo Y, Chang H, Qiao C, Xiao H, Li X, Li Y, Shen B, Zhang J: Defective anchoring of JNK1 in the cytoplasm by MKK7 in Jurkat cells is associated with resistance to Fas-mediated apoptosis. Mol Biol Cell. 2011 Jan 1;22(1):117-27. doi: 10.1091/mbc.E10-06-0492. Epub 2010 Dec 9. 21148294
  28. 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. 21856198
  29. Heo YS, Kim SK, Seo CI, Kim YK, Sung BJ, Lee HS, Lee JI, Park SY, Kim JH, Hwang KY, Hyun YL, Jeon YH, Ro S, Cho JM, Lee TG, Yang CH: Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125. EMBO J. 2004 Jun 2;23(11):2185-95. Epub 2004 May 13. 15141161
  30. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. 17344846