O08911 (MK12_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	367 AA.
Sequence status	Complete.
Protein existence	Evidence 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.5 Ref.7 Ref.8
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 By similarity. Interacts with SH3BP5, LIN7C, SCRIB and SYNJ2BP By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Mitochondrion By similarity. Note: Mitochondrial when associated with SH3BP5 By similarity. In skeletal muscle co-localizes with SNTA1 at the neuromuscular junction and throughout the sarcolemma By similarity.
Tissue specificity	Highly expressed in skeletal muscle. Also expressed in the heart, particularly in cardiac myocytes, lung, thymus and testes. 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.6 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 process	Cell cycle Stress response Transcription Transcription regulation
Cellular component	Cytoplasm Mitochondrion Nucleus
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW myoblast differentiation Inferred from electronic annotation. Source: Compara negative regulation of cell cycle Inferred from electronic annotation. Source: Compara peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW response to stress Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase activity Inferred from electronic annotation. Source: EC magnesium ion binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 367	367	Mitogen-activated protein kinase 12		PRO_0000186283
Regions
	Domain	27 – 311	285	Protein kinase
	Nucleotide binding	33 – 41	9	ATP By similarity
	Motif	183 – 185	3	TXY
Sites
	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 By similarity
	Modified residue	185	1	Phosphotyrosine; by MAP2K3 and MAP2K6 By similarity

Sequences

	Sequence		Length	Mass (Da)
	O08911 [UniParc]. Last modified July 1, 1997. Version 1. Checksum: AB36A40EF3C59981	FASTA	367	42,043
	10 20 30 40 50 60 MSSPPPARKG FYRQEVTKTA WEVRAVYQDL QPVGSGAYGA VCSAVDSRTG NKVAIKKLYR 70 80 90 100 110 120 PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDESLD 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 ITGTPPPEFV QKLQSAEAKN YMEGLPELEK KDFASVLTNA SPQAVNLLER MLVLDAEQRV 310 320 330 340 350 360 TAAEALTHPY FESLRDTEDE PKAQKYDDSF DDVDRTLEEW KRVTYKEVLS FKPPRQLGAR VPKETAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"Differential activation of p38MAPK isoforms by MKK6 and MKK3." Remy G., Risco A.M., Inesta-Vaquera F.A., Gonzalez-Teran B., Sabio G., Davis R.J., Cuenda A. Cell. Signal. 22:660-667(2010) [PubMed] [Europe PMC] [Abstract] 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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Y13439 mRNA. Translation: CAA73850.1. AK011286 mRNA. No translation available. BC021640 mRNA. Translation: AAH21640.1.
IPI	IPI00117172.
RefSeq	NP_038899.1. NM_013871.3.
UniGene	Mm.38343.
3D structure databases
ProteinModelPortal	O08911.
SMR	O08911. Positions 8-353.
ModBase	Search...
Protein-protein interaction databases
IntAct	O08911. 1 interaction.
MINT	MINT-1550872.
STRING	10090.ENSMUSP00000086207.
PTM databases
PhosphoSite	O08911.
Proteomic databases
PaxDb	O08911.
PRIDE	O08911.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000088827; ENSMUSP00000086207; ENSMUSG00000022610.
GeneID	29857.
KEGG	mmu:29857.
UCSC	uc007xfl.2. mouse.
Organism-specific databases
CTD	6300.
MGI	MGI:1353438. Mapk12.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00680000099969.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	O08911.
KO	K04441.
OMA	HEKLGED.
OrthoDB	EOG4R23V4.
Gene expression databases
ArrayExpress	O08911.
Bgee	O08911.
CleanEx	MM_MAPK12.
Genevestigator	O08911.
GermOnline	ENSMUSG00000022610. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR003527. MAP_kinase_CS. IPR008352. MAPK_p38. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
PRINTS	PR01773. P38MAPKINASE.
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 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. [Graphical view]
ProtoNet	Search...
Other
BindingDB	O08911.
ChEMBL	CHEMBL2445.
NextBio	307054.
SOURCE	Search...

Entry information

Entry name

MK12_MOUSE

Accession

Primary (citable) accession number: O08911
Secondary accession number(s): Q9D0M4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	July 1, 1997
Last modified:	May 29, 2013
This is version 123 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program