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Q63538 (MK12_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase 12

Short name=MAP kinase 12
Short name=MAPK 12
EC=2.7.11.24
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 names
Name:Mapk12
Synonyms:Sapk3
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length367 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.2 Ref.3

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Binds 2 magnesium ions.

Enzyme regulation

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. Ref.6

Subunit structure

Monomer. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with LIN7C, SCRIB, SYNJ2BP and SH3BP5. Ref.2 Ref.5 Ref.6

Subcellular location

Cytoplasm. Nucleus By similarity. Mitochondrion. Note: Mitochondrial when associated with SH3BP5. In skeletal muscle colocalizes with SNTA1 at the neuromuscular junction and throughout the sarcolemma. Ref.2 Ref.4 Ref.5

Tissue specificity

Highly expressed in skeletal muscle, lung and testes and also in the heart and thymus of both adult and neonatal rats. Ref.4

Domain

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

Post-translational modification

Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and MAP2K6/MKK6, which activates the enzyme. Ref.3

Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processCell cycle
Stress response
Transcription
Transcription regulation
   Cellular componentCytoplasm
Mitochondrion
Nucleus
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processMAPK cascade

Inferred from direct assay PubMed 16879317. Source: GOC

cell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

myoblast differentiation

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell cycle

Inferred from direct assay Ref.3. Source: UniProtKB

peptidyl-serine phosphorylation

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from direct assay PubMed 16879317. Source: RGD

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

response to stress

Inferred from electronic annotation. Source: UniProtKB-KW

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from direct assay Ref.4. Source: UniProtKB

mitochondrion

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from direct assay PubMed 16879317. Source: RGD

MAP kinase activity

Inferred from direct assay PubMed 16879317. Source: RGD

magnesium ion binding

Inferred from electronic annotation. Source: Ensembl

protein binding

Inferred from physical interaction PubMed 10212242. Source: IntAct

protein serine/threonine kinase activity

Inferred from direct assay Ref.3. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

SNTA1Q134245EBI-783937,EBI-717191From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 367367Mitogen-activated protein kinase 12
PRO_0000186284

Regions

Domain27 – 311285Protein kinase
Nucleotide binding33 – 419ATP By similarity
Motif183 – 1853TXY

Sites

Active site1531Proton acceptor By similarity
Binding site561ATP By similarity

Amino acid modifications

Modified residue1831Phosphothreonine; by MAP2K3 and MAP2K6 Ref.3
Modified residue1851Phosphotyrosine; by MAP2K3 and MAP2K6 Ref.3

Experimental info

Mutagenesis1831T → A: Loss of kinase activity. Ref.3
Mutagenesis1851Y → A: Loss of kinase activity. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q63538 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: B77193D9F45E1D4E

FASTA36741,985
        10         20         30         40         50         60 
MSSPPPARKG FYRQEVTKTA WEVRAVYQDL QPVGSGAYGA VCSAVDSRTG NKVAIKKLYR 

        70         80         90        100        110        120 
PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDETLD DFTDFYLVMP FMGTDLGKLM 

       130        140        150        160        170        180 
KHETLSEDRI QFLVYQMLKG LKYIHAAGVI HRDLKPGNLA VNEDCELKIL DFGLARQADS 

       190        200        210        220        230        240 
EMTGYVVTRW YRAPEVILNW MRYTQTVDIW SVGCIMAEMI TGKILFKGND HLDQLKEIMK 

       250        260        270        280        290        300 
VTGTPPPEFV QKLQSAEAKN YMEGLPELEK KDFASVLTNA SPQAVNLLEK MLVLDAEQRV 

       310        320        330        340        350        360 
TAAEALAHPY FESLRDTEDE PKAQKYDDSF DDVDRTLEEW KRVTYKEVLS FKPPRQLGAR 


VPKETAL 

« Hide

References

[1]"SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases."
Mertens S., Craxton M., Goedert M.
FEBS Lett. 383:273-276(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Skeletal muscle.
[2]"Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis."
Sumara G., Formentini I., Collins S., Sumara I., Windak R., Bodenmiller B., Ramracheya R., Caille D., Jiang H., Platt K.A., Meda P., Aebersold R., Rorsman P., Ricci R.
Cell 136:235-248(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SNTA1, FUNCTION IN PHOSPHORYLATION OF SNTA1, SUBCELLULAR LOCATION.
[3]"Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells."
Conrad P.W., Rust R.T., Han J., Millhorn D.E., Beitner-Johnson D.
J. Biol. Chem. 274:23570-23576(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-183 AND TYR-185, MUTAGENESIS OF THR-183 AND TYR-185.
[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: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[5]"Phosphorylation of the mitochondrial protein Sab by stress-activated protein kinase 3."
Court N.W., Kuo I., Quigley O., Bogoyevitch M.A.
Biochem. Biophys. Res. Commun. 319:130-137(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH SH3BP5.
[6]"Outer membrane protein 25-a mitochondrial anchor and inhibitor of stress-activated protein kinase-3."
Court N.W., Ingley E., Klinken S.P., Bogoyevitch M.A.
Biochim. Biophys. Acta 1744:68-75(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LIN7C; SCRIB AND SYNJ2BP, ENZYME REGULATION.
[7]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X96488 mRNA. Translation: CAA65342.1.
PIRS68680.
RefSeqNP_068514.1. NM_021746.1.
UniGeneRn.162968.

3D structure databases

ProteinModelPortalQ63538.
SMRQ63538. Positions 8-353.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid248795. 1 interaction.
IntActQ63538. 1 interaction.
STRING10116.ENSRNOP00000046455.

PTM databases

PhosphoSiteQ63538.

Proteomic databases

PRIDEQ63538.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000044376; ENSRNOP00000046455; ENSRNOG00000031233.
GeneID60352.
KEGGrno:60352.

Organism-specific databases

CTD6300.
RGD70975. Mapk12.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00680000099969.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidQ63538.
KOK04441.
OMANFKPPQT.
OrthoDBEOG7PCJGV.
PhylomeDBQ63538.
TreeFamTF105100.

Gene expression databases

GenevestigatorQ63538.

Family and domain databases

InterProIPR011009. 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_dom.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSPR01773. P38MAPKINASE.
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio612019.
PROQ63538.

Entry information

Entry nameMK12_RAT
AccessionPrimary (citable) accession number: Q63538
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: June 11, 2014
This is version 125 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families