Q63538 (MK12_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified November 13, 2013. Version 120. History...
Names and origin
|Protein names||Recommended name:|
Mitogen-activated protein kinase 12
Short name=MAP kinase 12
Short name=MAPK 12
Extracellular signal-regulated kinase 6
Mitogen-activated protein kinase p38 gamma
Short name=MAP kinase p38 gamma
Stress-activated protein kinase 3
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||367 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a protein = ADP + a phosphoprotein.
Binds 2 magnesium ions.
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
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
Highly expressed in skeletal muscle, lung and testes and also in the heart and thymus of both adult and neonatal rats. Ref.4
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
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.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 367||367||Mitogen-activated protein kinase 12||PRO_0000186284|
|Domain||27 – 311||285||Protein kinase|
|Nucleotide binding||33 – 41||9||ATP By similarity|
|Motif||183 – 185||3||TXY|
|Active site||153||1||Proton acceptor By similarity|
|Binding site||56||1||ATP By similarity|
Amino acid modifications
|Modified residue||183||1||Phosphothreonine; by MAP2K3 and MAP2K6 Ref.3|
|Modified residue||185||1||Phosphotyrosine; by MAP2K3 and MAP2K6 Ref.3|
|Mutagenesis||183||1||T → A: Loss of kinase activity. Ref.3|
|Mutagenesis||185||1||Y → A: Loss of kinase activity. Ref.3|
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|X96488 mRNA. Translation: CAA65342.1.|
|RefSeq||NP_068514.1. NM_021746.1. |
3D structure databases
|SMR||Q63538. Positions 8-353. |
Protein-protein interaction databases
|IntAct||Q63538. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000044376; ENSRNOP00000046455; ENSRNOG00000031233. |
|RGD||70975. Mapk12. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|PRINTS||PR01773. P38MAPKINASE. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS01351. MAPK. 1 hit. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. False negative.
|Accession||Primary (citable) accession number: Q63538|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families