MAP kinase-activated protein kinase 3

Details

Name
MAP kinase-activated protein kinase 3
Synonyms
  • 2.7.11.1
  • 3pK
  • Chromosome 3p kinase
  • MAPK-activated protein kinase 3
  • MAPKAP kinase 3
  • MAPKAP-K3
  • MAPKAPK-3
  • MK-3
Gene Name
MAPKAPK3
UniProtKB Entry
Q16644Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0012828|MAP kinase-activated protein kinase 3
MDGETAEEQGGPVPPPVAPGGPGLGGAPGGRREPKKYAVTDDYQLSKQVLGLGVNGKVLE
CFHRRTGQKCALKLLYDSPKARQEVDHHWQASGGPHIVCILDVYENMHHGKRCLLIIMEC
MEGGELFSRIQERGDQAFTEREAAEIMRDIGTAIQFLHSHNIAHRDVKPENLLYTSKEKD
AVLKLTDFGFAKETTQNALQTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGFP
PFYSNTGQAISPGMKRRIRLGQYGFPNPEWSEVSEDAKQLIRLLLKTDPTERLTITQFMN
HPWINQSMVVPQTPLHTARVLQEDKDHWDEVKEEMTSALATMRVDYDQVKIKDLKTSNNR
LLNKRRKKQAGSSSASQGCNNQ
Number of residues
382
Molecular Weight
42986.735
Theoretical pI
7.31
GO Classification
Functions
protein serine kinase activity
Processes
intracellular signal transduction
Components
cytoplasm
General Function
Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression
Specific Function
Atp binding
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0012829|MAP kinase-activated protein kinase 3 (MAPKAPK3)
ATGGATGGTGAAACAGCAGAGGAGCAGGGGGGCCCTGTGCCCCCGCCAGTTGCACCCGGC
GGACCCGGCTTGGGCGGTGCTCCGGGGGGGCGGCGGGAGCCCAAGAAGTACGCAGTGACC
GACGACTACCAGTTGTCCAAGCAGGTGCTGGGCCTGGGTGTGAACGGCAAAGTGCTGGAG
TGCTTCCATCGGCGCACTGGACAGAAGTGTGCCCTGAAGCTCCTGTATGACAGCCCCAAG
GCCCGGCAGGAGGTAGACCATCACTGGCAGGCTTCTGGCGGCCCCCATATTGTCTGCATC
CTGGATGTGTATGAGAACATGCACCATGGCAAGCGCTGTCTCCTCATCATCATGGAATGC
ATGGAAGGTGGTGAGTTGTTCAGCAGGATTCAGGAGCGTGGCGACCAGGCTTTCACTGAG
AGAGAAGCTGCAGAGATAATGCGGGATATTGGCACTGCCATCCAGTTTCTGCACAGCCAT
AACATTGCCCACCGAGATGTCAAGCCTGAAAACCTACTCTACACATCTAAGGAGAAAGAC
GCAGTGCTTAAGCTCACCGATTTTGGCTTTGCTAAGGAGACCACCCAAAATGCCCTGCAG
ACACCCTGCTATACTCCCTATTATGTGGCCCCTGAGGTCCTGGGTCCAGAGAAGTATGAC
AAGTCATGTGACATGTGGTCCCTGGGTGTCATCATGTACATCCTCCTTTGTGGCTTCCCA
CCCTTCTACTCCAACACGGGCCAGGCCATCTCCCCGGGGATGAAGAGGAGGATTCGCCTG
GGCCAGTACGGCTTCCCCAATCCTGAGTGGTCAGAAGTCTCTGAGGATGCCAAGCAGCTG
ATCCGCCTCCTGTTGAAGACAGACCCCACAGAGAGGCTGACCATCACTCAGTTCATGAAC
CACCCCTGGATCAACCAATCGATGGTAGTGCCACAGACCCCACTCCACACGGCCCGAGTG
CTGCAGGAGGACAAAGACCACTGGGACGAAGTCAAGGAGGAGATGACCAGTGCCTTGGCC
ACTATGCGGGTAGACTACGACCAGGTGAAGATCAAGGACCTGAAGACCTCTAACAACCGG
CTCCTCAACAAGAGGAGAAAAAAGCAGGCAGGCAGCTCCTCTGCCTCACAGGGCTGCAAC
AACCAGTAG
Chromosome Location
3
Locus
3p21.2
External Identifiers
ResourceLink
UniProtKB IDQ16644
UniProtKB Entry NameMAPK3_HUMAN
GenBank Protein ID1256005
GenBank Gene IDU43784
GeneCard IDMAPKAPK3
HGNC IDHGNC:6888
PDB ID(s)3FHR, 3FXW, 3R1N, 3SHE, 7NRB
KEGG IDhsa:7867
IUPHAR/Guide To Pharmacology ID2095
NCBI Gene ID7867
General References
  1. McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR: Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem. 1996 Apr 5;271(14):8488-92. [Article]
  2. Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S: 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region. Mol Cell Biol. 1996 Mar;16(3):868-76. [Article]
  3. 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. [Article]
  4. 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. [Article]
  5. Clifton AD, Young PR, Cohen P: A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress. FEBS Lett. 1996 Sep 2;392(3):209-14. [Article]
  6. Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M: Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation. J Biol Chem. 1999 Jul 2;274(27):18947-56. [Article]
  7. Neufeld B, Grosse-Wilde A, Hoffmeyer A, Jordan BW, Chen P, Dinev D, Ludwig S, Rapp UR: Serine/Threonine kinases 3pK and MAPK-activated protein kinase 2 interact with the basic helix-loop-helix transcription factor E47 and repress its transcriptional activity. J Biol Chem. 2000 Jul 7;275(27):20239-42. [Article]
  8. Zakowski V, Keramas G, Kilian K, Rapp UR, Ludwig S: Mitogen-activated 3p kinase is active in the nucleus. Exp Cell Res. 2004 Sep 10;299(1):101-9. [Article]
  9. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR: MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1. J Biol Chem. 2005 Feb 18;280(7):5178-87. Epub 2004 Nov 24. [Article]
  10. Mendoza H, Campbell DG, Burness K, Hastie J, Ronkina N, Shim JH, Arthur JS, Davis RJ, Gaestel M, Johnson GL, Ghosh S, Cohen P: Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem J. 2008 Feb 1;409(3):711-22. [Article]
  11. 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. [Article]
  12. Ronkina N, Menon MB, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, Gaestel M: MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochem Pharmacol. 2010 Dec 15;80(12):1915-20. doi: 10.1016/j.bcp.2010.06.021. Epub 2010 Jun 23. [Article]
  13. Ronkina N, Kotlyarov A, Gaestel M: MK2 and MK3--a pair of isoenzymes? Front Biosci. 2008 May 1;13:5511-21. [Article]
  14. 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. [Article]
  15. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [Article]
  16. Cheng R, Felicetti B, Palan S, Toogood-Johnson I, Scheich C, Barker J, Whittaker M, Hesterkamp T: High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand. Protein Sci. 2010 Jan;19(1):168-73. doi: 10.1002/pro.294. [Article]
  17. Barf T, Kaptein A, de Wilde S, van der Heijden R, van Someren R, Demont D, Schultz-Fademrecht C, Versteegh J, van Zeeland M, Seegers N, Kazemier B, van de Kar B, van Hoek M, de Roos J, Klop H, Smeets R, Hofstra C, Hornberg J, Oubrie A: Structure-based lead identification of ATP-competitive MK2 inhibitors. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3818-22. doi: 10.1016/j.bmcl.2011.04.018. Epub 2011 Apr 16. [Article]
  18. 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. [Article]

Associated Data

Bio-Entities
Bio-EntityType
MAP kinase-activated protein kinase 3 (Humans)protein
primary
Drug Relations
DrugDrug groupPharmacological action?TypeActionsDetails
2-[2-(2-FLUOROPHENYL)PYRIDIN-4-YL]-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONEexperimentalunknowntargetDetails
2-(2-QUINOLIN-3-YLPYRIDIN-4-YL)-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONEexperimentalunknowntargetDetails