Dual specificity mitogen-activated protein kinase kinase 4

NameDual specificity mitogen-activated protein kinase kinase 4
Synonyms
  • 2.7.12.2
  • c-Jun N-terminal kinase kinase 1
  • JNK-activating kinase 1
  • JNKK
  • JNKK1
  • MAP kinase kinase 4
  • MAPK/ERK kinase 4
  • MEK 4
  • MEK4
  • MKK4
  • PRKMK4
  • SAPK kinase 1
  • SAPK/ERK kinase 1
  • SAPKK-1
  • SAPKK1
  • SEK1
  • SERK1
  • SKK1
  • Stress-activated protein kinase kinase 1
Gene NameMAP2K4
OrganismHuman
Amino acid sequence
>lcl|BSEQ0009089|Dual specificity mitogen-activated protein kinase kinase 4
MAAPSPSGGGGSGGGSGSGTPGPVGSPAPGHPAVSSMQGKRKALKLNFANPPFKSTARFT
LNPNPTGVQNPHIERLRTHSIESSGKLKISPEQHWDFTAEDLKDLGEIGRGAYGSVNKMV
HKPSGQIMAVKRIRSTVDEKEQKQLLMDLDVVMRSSDCPYIVQFYGALFREGDCWICMEL
MSTSFDKFYKYVYSVLDDVIPEEILGKITLATVKALNHLKENLKIIHRDIKPSNILLDRS
GNIKLCDFGISGQLVDSIAKTRDAGCRPYMAPERIDPSASRQGYDVRSDVWSLGITLYEL
ATGRFPYPKWNSVFDQLTQVVKGDPPQLSNSEEREFSPSFINFVNLCLTKDESKRPKYKE
LLKHPFILMYEERAVEVACYVCKILDQMPATPSSPMYVD
Number of residues399
Molecular Weight44287.34
Theoretical pINot Available
GO Classification
Functions
  • protein serine/threonine kinase activity
  • protein tyrosine kinase activity
  • ATP binding
  • protein kinase activity
Processes
  • toll-like receptor 5 signaling pathway
  • toll-like receptor 9 signaling pathway
  • toll-like receptor signaling pathway
  • toll-like receptor TLR1
  • innate immune response
  • toll-like receptor TLR6
  • Fc-epsilon receptor signaling pathway
  • TRIF-dependent toll-like receptor signaling pathway
  • cellular response to mechanical stimulus
  • apoptotic process
  • JNK cascade
  • MyD88-dependent toll-like receptor signaling pathway
  • MyD88-independent toll-like receptor signaling pathway
  • stress-activated MAPK cascade
  • toll-like receptor 10 signaling pathway
  • signal transduction
  • toll-like receptor 2 signaling pathway
  • toll-like receptor 3 signaling pathway
  • toll-like receptor 4 signaling pathway
Components
  • nucleus
  • cytosol
General FunctionProtein tyrosine kinase activity
Specific FunctionDual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein IDNot Available
UniProtKB IDP45985
UniProtKB Entry NameMP2K4_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0017683|Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4)
ATGGCGGCTCCGAGCCCGAGCGGCGGCGGCGGCTCCGGGGGCGGCAGCGGCAGCGGCACC
CCCGGCCCCGTAGGGTCCCCGGCGCCAGGCCACCCGGCCGTCAGCAGCATGCAGGGCTTT
CAGATAAACTTCTGTGAAAAGGCACAAAGTAAACGCAAAGCACTGAAGTTGAATTTTGCA
AATCCACCTTTCAAATCTACAGCAAGGTTTACTCTGAATCCCAATCCTACAGGAGTTCAA
AACCCACACATAGAGAGACTGAGAACACACAGCATTGAGTCATCAGGAAAACTGAAGATC
TCCCCTGAACAACACTGGGATTTCACTGCAGAGGACTTGAAAGACCTTGGAGAAATTGGA
CGAGGAGCTTATGGTTCTGTCAACAAAATGGTCCACAAACCAAGTGGGCAAATAATGGCA
GTTAAAAGAATTCGGTCAACAGTGGATGAAAAAGAACAAAAACAACTTCTTATGGATTTG
GATGTAGTAATGCGGAGTAGTGATTGCCCATACATTGTTCAGTTTTATGGTGCACTCTTC
AGAGAGGGTGACTGTTGGATCTGTATGGAACTCATGTCTACCTCGTTTGATAAGTTTTAC
AAATATGTATATAGTGTATTAGATGATGTTATTCCAGAAGAAATTTTAGGCAAAATCACT
TTAGCAACTGTGAAAGCACTAAACCACTTAAAAGAAAACTTGAAAATTATTCACAGAGAT
ATCAAACCTTCCAATATTCTTCTGGACAGAAGTGGAAATATTAAGCTCTGTGACTTCGGC
ATCAGTGGACAGCTTGTGGACTCTATTGCCAAGACAAGAGATGCTGGCTGTAGGCCATAC
ATGGCACCTGAAAGAATAGACCCAAGCGCATCACGACAAGGATATGATGTCCGCTCTGAT
GTCTGGAGTTTGGGGATCACATTGTATGAGTTGGCCACAGGCCGATTTCCTTATCCAAAG
TGGAATAGTGTATTTGATCAACTAACACAAGTCGTGAAAGGAGATCCTCCGCAGCTGAGT
AATTCTGAGGAAAGGGAATTCTCCCCGAGTTTCATCAACTTTGTCAACTTGTGCCTTACG
AAGGATGAATCCAAAAGGCCAAAGTATAAAGAGCTTCTGAAACATCCCTTTATTTTGATG
TATGAAGAACGTGCCGTTGAGGTCGCATGCTATGTTTGTAAAATCCTGGATCAAATGCCA
GCTACTCCCAGCTCTCCCATGTATGTCGATTGA
GenBank Gene IDNot Available
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:6844
Chromosome Location17
LocusNot Available
References
  1. 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
  2. Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M: Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286-90. 7716521
  3. Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo CJ, Hruban RH, Kern SE: Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 1998 Jun 1;58(11):2339-42. 9622070
  4. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  5. Zody MC, Garber M, Adams DJ, Sharpe T, Harrow J, Lupski JR, Nicholson C, Searle SM, Wilming L, Young SK, Abouelleil A, Allen NR, Bi W, Bloom T, Borowsky ML, Bugalter BE, Butler J, Chang JL, Chen CK, Cook A, Corum B, Cuomo CA, de Jong PJ, DeCaprio D, Dewar K, FitzGerald M, Gilbert J, Gibson R, Gnerre S, Goldstein S, Grafham DV, Grocock R, Hafez N, Hagopian DS, Hart E, Norman CH, Humphray S, Jaffe DB, Jones M, Kamal M, Khodiyar VK, LaButti K, Laird G, Lehoczky J, Liu X, Lokyitsang T, Loveland J, Lui A, Macdonald P, Major JE, Matthews L, Mauceli E, McCarroll SA, Mihalev AH, Mudge J, Nguyen C, Nicol R, O'Leary SB, Osoegawa K, Schwartz DC, Shaw-Smith C, Stankiewicz P, Steward C, Swarbreck D, Venkataraman V, Whittaker CA, Yang X, Zimmer AR, Bradley A, Hubbard T, Birren BW, Rogers J, Lander ES, Nusbaum C: DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. Nature. 2006 Apr 20;440(7087):1045-9. 16625196
  6. 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
  7. Tibbles LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR, Lassam NJ: MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EMBO J. 1996 Dec 16;15(24):7026-35. 9003778
  8. Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C: Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000 Dec 15;352 Pt 3:739-45. 11104681
  9. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ: Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science. 2000 Nov 24;290(5496):1574-7. 11090355
  10. Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, Yoshioka K, Ichijo H: Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade. J Biol Chem. 2002 Oct 25;277(43):40703-9. Epub 2002 Aug 19. 12189133
  11. Ho DT, Bardwell AJ, Abdollahi M, Bardwell L: A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates. J Biol Chem. 2003 Aug 29;278(35):32662-72. Epub 2003 Jun 3. 12788955
  12. Takekawa M, Tatebayashi K, Saito H: Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol Cell. 2005 Apr 29;18(3):295-306. 15866172
  13. 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
  14. Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem. 2009 Jun 1;81(11):4493-501. doi: 10.1021/ac9004309. 19413330
  15. Li X, MacLeod R, Dunlop AJ, Edwards HV, Advant N, Gibson LC, Devine NM, Brown KM, Adams DR, Houslay MD, Baillie GS: A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex. FEBS Lett. 2009 Oct 20;583(20):3310-6. doi: 10.1016/j.febslet.2009.09.035. Epub 2009 Sep 24. 19782076
  16. Raman M, Chen W, Cobb MH: Differential regulation and properties of MAPKs. Oncogene. 2007 May 14;26(22):3100-12. 17496909
  17. 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
  18. Asaoka Y, Nishina H: Diverse physiological functions of MKK4 and MKK7 during early embryogenesis. J Biochem. 2010 Oct;148(4):393-401. doi: 10.1093/jb/mvq098. Epub 2010 Aug 27. 20801953
  19. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. 20068231
  20. 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
  21. Haeusgen W, Herdegen T, Waetzig V: The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. Eur J Cell Biol. 2011 Jun-Jul;90(6-7):536-44. doi: 10.1016/j.ejcb.2010.11.008. Epub 2011 Feb 18. 21333379
  22. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. 24275569
  23. Matsumoto T, Kinoshita T, Kirii Y, Yokota K, Hamada K, Tada T: Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state. Biochem Biophys Res Commun. 2010 Sep 24;400(3):369-73. doi: 10.1016/j.bbrc.2010.08.071. Epub 2010 Aug 21. 20732303
  24. 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