Mitogen-activated protein kinase 12

Details

Name
Mitogen-activated protein kinase 12
Synonyms
  • 2.7.11.24
  • ERK-6
  • ERK6
  • Extracellular signal-regulated kinase 6
  • MAP kinase 12
  • MAP kinase p38 gamma
  • Mitogen-activated protein kinase p38 gamma
  • SAPK3
  • Stress-activated protein kinase 3
Gene Name
MAPK12
Organism
Humans
Amino acid sequence
>lcl|BSEQ0005465|Mitogen-activated protein kinase 12
MSSPPPARSGFYRQEVTKTAWEVRAVYRDLQPVGSGAYGAVCSAVDGRTGAKVAIKKLYR
PFQSELFAKRAYRELRLLKHMRHENVIGLLDVFTPDETLDDFTDFYLVMPFMGTDLGKLM
KHEKLGEDRIQFLVYQMLKGLRYIHAAGIIHRDLKPGNLAVNEDCELKILDFGLARQADS
EMTGYVVTRWYRAPEVILNWMRYTQTVDIWSVGCIMAEMITGKTLFKGSDHLDQLKEIMK
VTGTPPAEFVQRLQSDEAKNYMKGLPELEKKDFASILTNASPLAVNLLEKMLVLDAEQRV
TAGEALAHPYFESLHDTEDEPQVQKYDDSFDDVDRTLDEWKRVTYKEVLSFKPPRQLGAR
VSKETPL
Number of residues
367
Molecular Weight
41939.84
Theoretical pI
6.33
GO Classification
Functions
ATP binding / magnesium ion binding / MAP kinase activity / protein serine/threonine kinase activity
Processes
cell cycle arrest / DNA damage induced protein phosphorylation / MAPK cascade / mitochondrion organization / muscle cell differentiation / muscle organ development / myoblast differentiation / neurotrophin TRK receptor signaling pathway / organelle organization / peptidyl-serine phosphorylation / positive regulation of muscle cell differentiation / positive regulation of peptidase activity / Ras protein signal transduction / regulation of transcription, DNA-templated / signal transduction / transcription, DNA-templated / vascular endothelial growth factor receptor signaling pathway
Components
cytoplasm / cytosol / mitochondrion / nucleoplasm
General Function
Protein serine/threonine kinase activity
Specific Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0021343|Mitogen-activated protein kinase 12 (MAPK12)
ATGAGCTCTCCGCCGCCCGCCCGCAGTGGCTTTTACCGCCAGGAGGTGACCAAGACGGCC
TGGGAGGTGCGCGCCGTGTACCGGGACCTGCAGCCCGTGGGCTCGGGCGCCTACGGCGCG
GTGTGCTCGGCCGTGGACGGCCGCACCGGCGCTAAGGTGGCCATCAAGAAGCTGTATCGG
CCTTTCCAGTCCGAGCTGTTCGCCAAGCGCGCCTACCGCGAGCTGCGCCTGCTCAAGCAC
ATGCGCCACGAGAACGTGATCGGGCTGCTGGACGTATTCACTCCTGATGAGACCCTGGAT
GACTTCACGGACTTTTACCTGGTGATGCCGTTCATGGGCACCGACCTGGGCAAGCTCATG
AAACATGAGAAGCTAGGCGAGGACCGGATCCAGTTCCTCGTGTACCAGATGCTGAAGGGG
CTGAGGGACCTGAAGCCCGGCAACCTGGCTGTGAACGAAGACTGTGAGCTGAAGATCCTG
GACTTCGGCCTGGCCAGGCAGGCAGACAGTGAGATGACTGGGTACGTGGTGACCCGGTGG
TACCGGGCTCCCGAGGTCATCTTGAATTGGATGCGCTACACGCAGACGGTGGACATCTGG
TCTGTGGGCTGCATCATGGCGGAGATGATCACAGGCAAGACGCTGTTCAAGGGCAGCGAC
CACCTGGACCAGCTGAAGGAGATCATGAAGGTGACGGGGACGCCTCCGGCTGAGTTTGTG
CAGCGGCTGCAGAGCGATGAGGCCAAGAACTACATGAAGGGCCTCCCCGAATTGGAGAAG
AAGGATTTTGCCTCTATCCTGACCAATGCAAGCCCTCTGGCTGTGAACCTCCTGGAGAAG
ATGCTGGTGCTGGACGCGGAGCAGCGGGTGACGGCAGGCGAGGCGCTGGCCCATCCCTAC
TTCGAGTCCCTGCACGACACGGAAGATGAGCCCCAGGTCCAGAAGTATGATGACTCCTTT
GACGACGTTGACCGCACACTGGATGAATGGAAGCGTGTTACTTACAAAGAGGTGCTCAGC
TTCAAGCCTCCCCGGCAGCTGGGGGCCAGGGTCTCCAAGGAGACGCCTCTGTGA
Chromosome Location
22
Locus
22q13.33
External Identifiers
ResourceLink
UniProtKB IDP53778
UniProtKB Entry NameMK12_HUMAN
GenBank Gene IDX79483
GenAtlas IDMAPK12
HGNC IDHGNC:6874
General References
  1. Lechner C, Zahalka MA, Giot JF, Moller NP, Ullrich A: ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355-9. [Article]
  2. Goedert M, Hasegawa J, Craxton M, Leversha MA, Clegg S: Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization. Genomics. 1997 May 1;41(3):501-2. [Article]
  3. Li Z, Jiang Y, Ulevitch RJ, Han J: The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun. 1996 Nov 12;228(2):334-40. [Article]
  4. Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I: A genome annotation-driven approach to cloning the human ORFeome. Genome Biol. 2004;5(10):R84. Epub 2004 Sep 30. [Article]
  5. Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP, et al.: The DNA sequence of human chromosome 22. Nature. 1999 Dec 2;402(6761):489-95. [Article]
  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. [Article]
  7. Enslen H, Raingeaud J, Davis RJ: Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998 Jan 16;273(3):1741-8. [Article]
  8. Hasegawa M, Cuenda A, Spillantini MG, Thomas GM, Buee-Scherrer V, Cohen P, Goedert M: Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition. J Biol Chem. 1999 Apr 30;274(18):12626-31. [Article]
  9. Alonso G, Ambrosino C, Jones M, Nebreda AR: Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. J Biol Chem. 2000 Dec 22;275(51):40641-8. [Article]
  10. Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J: Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000 Jul;20(13):4543-52. [Article]
  11. Court NW, dos Remedios CG, Cordell J, Bogoyevitch MA: Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3). J Mol Cell Cardiol. 2002 Apr;34(4):413-26. [Article]
  12. Wiltshire C, Matsushita M, Tsukada S, Gillespie DA, May GH: A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5), associates with mitochondria. Biochem J. 2002 Nov 1;367(Pt 3):577-85. [Article]
  13. Ho RC, Alcazar O, Fujii N, Hirshman MF, Goodyear LJ: p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2004 Feb;286(2):R342-9. Epub 2003 Oct 30. [Article]
  14. Diskin R, Askari N, Capone R, Engelberg D, Livnah O: Active mutants of the human p38alpha mitogen-activated protein kinase. J Biol Chem. 2004 Nov 5;279(45):47040-9. Epub 2004 Jul 28. [Article]
  15. Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Chen G: p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007 Oct 26;282(43):31398-408. Epub 2007 Aug 27. [Article]
  16. Sabio G, Cerezo-Guisado MI, Del Reino P, Inesta-Vaquera FA, Rousseau S, Arthur JS, Campbell DG, Centeno F, Cuenda A: p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock. J Cell Sci. 2010 Aug 1;123(Pt 15):2596-604. doi: 10.1242/jcs.066514. Epub 2010 Jul 6. [Article]
  17. 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]
  18. Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C, Pouwels J, Laine L, Kallio MJ: Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death. J Cell Sci. 2011 Jan 15;124(Pt 2):216-27. doi: 10.1242/jcs.068254. Epub 2010 Dec 15. [Article]
  19. Meng F, Zhang H, Liu G, Kreike B, Chen W, Sethi S, Miller FR, Wu G: p38gamma mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer. Neoplasia. 2011 May;13(5):472-82. [Article]
  20. Cuadrado A, Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010 Aug 1;429(3):403-17. doi: 10.1042/BJ20100323. [Article]
  21. Bellon S, Fitzgibbon MJ, Fox T, Hsiao HM, Wilson KP: The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure. 1999 Sep 15;7(9):1057-65. [Article]
  22. 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]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02482PhosphonothreonineexperimentalunknownDetails
DB04395Phosphoaminophosphonic Acid-Adenylate EsterexperimentalunknownDetails
DB05403CEP-1347investigationalunknownDetails
DB05157KC706investigationalunknownDetails
DB01017Minocyclineapproved, investigationalunknowninhibitorDetails