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Protein

Mitogen-activated protein kinase 12

Gene

Mapk12

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+Note: Binds 2 magnesium ions.

Enzyme regulationi

Activated by phosphorylation on threonine and tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK12 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK12 activator in response to TNF-alpha.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei56 – 561ATPPROSITE-ProRule annotation
Active sitei153 – 1531Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi33 – 419ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Cell cycle, Stress response, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_271763. DSCAM interactions.
REACT_296095. p38MAPK events.
REACT_301153. NOD1/2 Signaling Pathway.
REACT_304595. CDO in myogenesis.
REACT_315885. VEGFA-VEGFR2 Pathway.
REACT_321345. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 12 (EC:2.7.11.24)
Short name:
MAP kinase 12
Short name:
MAPK 12
Alternative name(s):
Extracellular signal-regulated kinase 6
Short name:
ERK-6
Mitogen-activated protein kinase p38 gamma
Short name:
MAP kinase p38 gamma
Stress-activated protein kinase 3
Gene namesi
Name:Mapk12
Synonyms:Sapk3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:1353438. Mapk12.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity
  • Mitochondrion By similarity

  • Note: Mitochondrial when associated with SH3BP5. In skeletal muscle colocalizes with SNTA1 at the neuromuscular junction and throughout the sarcolemma.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 367367Mitogen-activated protein kinase 12PRO_0000186283Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei183 – 1831Phosphothreonine; by MAP2K3 and MAP2K6By similarity
Modified residuei185 – 1851Phosphotyrosine; by MAP2K3 and MAP2K6By similarity

Post-translational modificationi

Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and MAP2K6/MKK6, which activates the enzyme.1 Publication
Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiO08911.
PaxDbiO08911.
PRIDEiO08911.

PTM databases

PhosphoSiteiO08911.

Expressioni

Tissue specificityi

Highly expressed in skeletal muscle. Also expressed in the heart, particularly in cardiac myocytes, lung, thymus and testes.1 Publication

Gene expression databases

BgeeiO08911.
CleanExiMM_MAPK12.
ExpressionAtlasiO08911. baseline and differential.
GenevisibleiO08911. MM.

Interactioni

Subunit structurei

Monomer. Interacts with the PDZ domain of the syntrophin SNTA1 (By similarity). Interacts with SH3BP5, LIN7C, SCRIB and SYNJ2BP (By similarity).By similarity

Protein-protein interaction databases

IntActiO08911. 1 interaction.
MINTiMINT-1550872.
STRINGi10090.ENSMUSP00000086207.

Structurei

3D structure databases

ProteinModelPortaliO08911.
SMRiO08911. Positions 8-353.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini27 – 311285Protein kinasePROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi183 – 1853TXY

Domaini

The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00550000074271.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiO08911.
KOiK04441.
OMAiMKHEKLG.
OrthoDBiEOG7PCJGV.
PhylomeDBiO08911.
TreeFamiTF105100.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008352. MAPK_p38.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSiPR01773. P38MAPKINASE.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O08911-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSPPPARKG FYRQEVTKTA WEVRAVYQDL QPVGSGAYGA VCSAVDSRTG
60 70 80 90 100
NKVAIKKLYR PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDESLD
110 120 130 140 150
DFTDFYLVMP FMGTDLGKLM KHETLSEDRI QFLVYQMLKG LKYIHAAGVI
160 170 180 190 200
HRDLKPGNLA VNEDCELKIL DFGLARQADS EMTGYVVTRW YRAPEVILNW
210 220 230 240 250
MRYTQTVDIW SVGCIMAEMI TGKILFKGND HLDQLKEIMK ITGTPPPEFV
260 270 280 290 300
QKLQSAEAKN YMEGLPELEK KDFASVLTNA SPQAVNLLER MLVLDAEQRV
310 320 330 340 350
TAAEALTHPY FESLRDTEDE PKAQKYDDSF DDVDRTLEEW KRVTYKEVLS
360
FKPPRQLGAR VPKETAL
Length:367
Mass (Da):42,043
Last modified:July 1, 1997 - v1
Checksum:iAB36A40EF3C59981
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y13439 mRNA. Translation: CAA73850.1.
AK011286 mRNA. No translation available.
BC021640 mRNA. Translation: AAH21640.1.
CCDSiCCDS27740.1.
RefSeqiNP_038899.1. NM_013871.3.
UniGeneiMm.38343.

Genome annotation databases

EnsembliENSMUST00000088827; ENSMUSP00000086207; ENSMUSG00000022610.
GeneIDi29857.
KEGGimmu:29857.
UCSCiuc007xfl.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y13439 mRNA. Translation: CAA73850.1.
AK011286 mRNA. No translation available.
BC021640 mRNA. Translation: AAH21640.1.
CCDSiCCDS27740.1.
RefSeqiNP_038899.1. NM_013871.3.
UniGeneiMm.38343.

3D structure databases

ProteinModelPortaliO08911.
SMRiO08911. Positions 8-353.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiO08911. 1 interaction.
MINTiMINT-1550872.
STRINGi10090.ENSMUSP00000086207.

Chemistry

ChEMBLiCHEMBL2111473.

PTM databases

PhosphoSiteiO08911.

Proteomic databases

MaxQBiO08911.
PaxDbiO08911.
PRIDEiO08911.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000088827; ENSMUSP00000086207; ENSMUSG00000022610.
GeneIDi29857.
KEGGimmu:29857.
UCSCiuc007xfl.2. mouse.

Organism-specific databases

CTDi6300.
MGIiMGI:1353438. Mapk12.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00550000074271.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiO08911.
KOiK04441.
OMAiMKHEKLG.
OrthoDBiEOG7PCJGV.
PhylomeDBiO08911.
TreeFamiTF105100.

Enzyme and pathway databases

ReactomeiREACT_271763. DSCAM interactions.
REACT_296095. p38MAPK events.
REACT_301153. NOD1/2 Signaling Pathway.
REACT_304595. CDO in myogenesis.
REACT_315885. VEGFA-VEGFR2 Pathway.
REACT_321345. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.

Miscellaneous databases

NextBioi307054.
PROiO08911.
SOURCEiSearch...

Gene expression databases

BgeeiO08911.
CleanExiMM_MAPK12.
ExpressionAtlasiO08911. baseline and differential.
GenevisibleiO08911. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008352. MAPK_p38.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSiPR01773. P38MAPKINASE.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Goedert M., Craxton M.
    Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Skeletal muscle.
  2. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Embryo.
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
  4. "Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3)."
    Court N.W., dos Remedios C.G., Cordell J., Bogoyevitch M.A.
    J. Mol. Cell. Cardiol. 34:413-426(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  5. "p38-{gamma}-dependent gene silencing restricts entry into the myogenic differentiation program."
    Gillespie M.A., Le Grand F., Scime A., Kuang S., von Maltzahn J., Seale V., Cuenda A., Ranish J.A., Rudnicki M.A.
    J. Cell Biol. 187:991-1005(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. Cited for: PHOSPHORYLATION, ENZYME REGULATION.
  7. "p38gamma regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage."
    Wu C.C., Wu X., Han J., Sun P.
    Protein Cell 1:573-583(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. "Evidence of p38gamma and p38delta involvement in cell transformation processes."
    Cerezo-Guisado M.I., del Reino P., Remy G., Kuma Y., Arthur J.S., Gallego-Ortega D., Cuenda A.
    Carcinogenesis 32:1093-1099(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. "Mechanisms and functions of p38 MAPK signalling."
    Cuadrado A., Nebreda A.R.
    Biochem. J. 429:403-417(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.

Entry informationi

Entry nameiMK12_MOUSE
AccessioniPrimary (citable) accession number: O08911
Secondary accession number(s): Q9D0M4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: July 1, 1997
Last modified: July 22, 2015
This is version 143 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.