P31938 (MP2K1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dual specificity mitogen-activated protein kinase kinase 1
Short name=MAP kinase kinase 1
Short name=MAPKK 1
EC=2.7.12.2

Alternative name(s):
ERK activator kinase 1
MAPK/ERK kinase 1
Short name=MEK 1

Gene names

Name:	Map2k1
Synonyms:	Mek1, Prkmk1

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	393 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis. Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A. Ref.5
Subunit structure	Found in a complex with at least BRAF, HRAS1, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with LAMTOR3, MAPK1/ERK2, RAF1, PPARG AND VRK2 By similarity. Interacts with ARRB2 and MORG1. Forms a heterodimer with MAP2K2/MEK2. Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity. Ref.7 Ref.8
Subcellular location	Cytoplasm › cytoskeleton › centrosome By similarity. Cytoplasm › cytoskeleton › spindle pole body By similarity. Cytoplasm By similarity. Nucleus By similarity. Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis By similarity.
Domain	The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1 By similarity.
Post-translational modification	Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (RAF or MEKK1) positively regulates kinase activity. Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK. MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK. Ref.5 Ref.8
Disruption phenotype	Affects fibroblast shape and impairs haptotaxis and adhesion-dependent ERK-signaling. Ref.8
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm Cytoskeleton Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Golgi inheritance Inferred from electronic annotation. Source: Compara cell cycle arrest Inferred from electronic annotation. Source: Compara cell motility Inferred from mutant phenotype PubMed 10209122. Source: MGI cell proliferation Inferred from electronic annotation. Source: Compara cellular senescence Inferred from electronic annotation. Source: Compara keratinocyte differentiation Inferred from mutant phenotype PubMed 11841548. Source: MGI labyrinthine layer development Inferred from mutant phenotype PubMed 10209122. Source: MGI melanosome transport Inferred from electronic annotation. Source: Compara mitosis Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of homotypic cell-cell adhesion Inferred from electronic annotation. Source: Compara neuron differentiation Inferred from mutant phenotype PubMed 15145949. Source: MGI neuron projection morphogenesis Inferred from electronic annotation. Source: Compara placenta blood vessel development Inferred from mutant phenotype PubMed 10209122. Source: MGI positive regulation of Ras GTPase activity Inferred from electronic annotation. Source: Compara positive regulation of Ras protein signal transduction Inferred from sequence orthology PubMed 19029245. Source: MGI positive regulation of cell differentiation Inferred from direct assay PubMed 16908534. Source: MGI positive regulation of cell migration Inferred from electronic annotation. Source: Compara positive regulation of transcription elongation from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara protein heterooligomerization Inferred from electronic annotation. Source: Compara regulation of Golgi inheritance Traceable author statement Ref.11. Source: UniProtKB regulation of early endosome to late endosome transport Traceable author statement Ref.11. Source: UniProtKB regulation of stress-activated MAPK cascade Traceable author statement Ref.11. Source: UniProtKB regulation of vascular smooth muscle contraction Inferred from electronic annotation. Source: Compara response to axon injury Inferred from electronic annotation. Source: Compara response to glucocorticoid stimulus Inferred from electronic annotation. Source: Compara response to oxidative stress Inferred from electronic annotation. Source: Compara vesicle transport along microtubule Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi apparatus Traceable author statement Ref.11. Source: UniProtKB axon part Inferred from electronic annotation. Source: Compara cell cortex Inferred from electronic annotation. Source: Compara cytosol Traceable author statement Ref.11. Source: UniProtKB dendrite cytoplasm Inferred from electronic annotation. Source: Compara early endosome Traceable author statement Ref.11. Source: UniProtKB focal adhesion Traceable author statement Ref.11. Source: UniProtKB late endosome Traceable author statement Ref.11. Source: UniProtKB mitochondrion Traceable author statement Ref.11. Source: UniProtKB nucleus Traceable author statement Ref.11. Source: UniProtKB perikaryon Inferred from electronic annotation. Source: Compara perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara plasma membrane Inferred from electronic annotation. Source: Compara spindle pole body Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase activity Inferred from mutant phenotype PubMed 11841548. Source: MGI protein serine/threonine kinase activator activity Inferred from electronic annotation. Source: Compara protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW receptor signaling protein tyrosine phosphatase activity Inferred from mutant phenotype PubMed 15896720. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 393	392	Dual specificity mitogen-activated protein kinase kinase 1		PRO_0000086366
Regions
	Domain	68 – 361	294	Protein kinase
	Nucleotide binding	74 – 82	9	ATP By similarity
	Region	270 – 307	38	RAF1-binding By similarity
	Compositional bias	262 – 307	46	Pro-rich
Sites
	Active site	190	1	Proton acceptor By similarity
	Binding site	97	1	ATP By similarity
	Site	8 – 9	2	Cleavage; by anthrax lethal factor By similarity
Amino acid modifications
	Modified residue	218	1	Phosphoserine; by RAF By similarity
	Modified residue	222	1	Phosphoserine; by RAF By similarity
	Modified residue	286	1	Phosphothreonine By similarity
	Modified residue	292	1	Phosphothreonine; by MAPK1 By similarity
	Modified residue	298	1	Phosphoserine; by PAK By similarity
Experimental info
	Mutagenesis	78	1	N → G: Impairs interaction with MAP2K2/MEK2. Ref.8
	Mutagenesis	292	1	T → A: Results in hyperphosphorylation of the RAF-dependent sites and prolonged ERK phosphorylation. Ref.8
	Mutagenesis	292	1	T → D: Results in hypophosphorylation of the RAF-dependent sites and faster ERK inactivation. Ref.8
	Sequence conflict	374	1	W → Q AA sequence Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P31938 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 01D1D18572AE40E7	FASTA	393	43,474
	10 20 30 40 50 60 MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL EAFLTQKQKV 70 80 90 100 110 120 GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH LEIKPAIRNQ IIRELQVLHE 130 140 150 160 170 180 CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS LDQVLKKAGR IPEQILGKVS IAVIKGLTYL 190 200 210 220 230 240 REKHKIMHRD VKPSNILVNS RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY 250 260 270 280 290 300 SVQSDIWSMG LSLVEMAVGR YPIPPPDAKE LELLFGCHVE GDAAETPPRP RTPGRPLSSY 310 320 330 340 350 360 GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF 370 380 390 IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA ASI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product." Crews C.M., Alessandrini A., Erikson R.L. Science 258:478-480(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[2]	"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: C57BL/6. Tissue: Brain.
[3]	"Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product." Crews C.M., Erikson R.L. Proc. Natl. Acad. Sci. U.S.A. 89:8205-8209(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 4-20; 71-84; 114-136; 206-234 AND 363-384. Tissue: T-cell.
[4]	Lubec G., Klug S. Submitted (MAR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 206-227; 270-291 AND 325-340, MASS SPECTROMETRY. Tissue: Hippocampus.
[5]	"A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf." Lange-Carter C.A., Pleiman C.M., Gardner A.M., Blumer K.J., Johnson G.L. Science 260:315-319(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AND ENZYME REGULATION.
[6]	"Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor." Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R., Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D., Vande Woude G.F. Science 280:734-737(1998) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[7]	"Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists." Vomastek T., Schaeffer H.-J., Tarcsafalvi A., Smolkin M.E., Bissonette E.A., Weber M.J. Proc. Natl. Acad. Sci. U.S.A. 101:6981-6986(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MORG1.
[8]	"A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal." Catalanotti F., Reyes G., Jesenberger V., Galabova-Kovacs G., de Matos Simoes R., Carugo O., Baccarini M. Nat. Struct. Mol. Biol. 16:294-303(2009) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH MAP2K2/MEK2, PHOSPHORYLATION AT THR-292, MUTAGENESIS OF ASN-78 AND THR-292.
[9]	"Signaling by dual specificity kinases." Dhanasekaran N., Premkumar Reddy E. Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[10]	"The RAF proteins take centre stage." Wellbrock C., Karasarides M., Marais R. Nat. Rev. Mol. Cell Biol. 5:875-885(2004) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ENZYME REGULATION.
[11]	"The ERK signaling cascade--views from different subcellular compartments." Yao Z., Seger R. BioFactors 35:407-416(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[12]	"The ERK cascade: distinct functions within various subcellular organelles." Wortzel I., Seger R. Genes Cancer 2:195-209(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L02526 mRNA. Translation: AAA39523.1. BC054754 mRNA. Translation: AAH54754.1.
IPI	IPI00466610.
PIR	I59571.
RefSeq	NP_032953.1. NM_008927.3.
UniGene	Mm.248907.
3D structure databases
ProteinModelPortal	P31938.
SMR	P31938. Positions 39-381.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-467N.
IntAct	P31938. 3 interactions.
STRING	10090.ENSMUSP00000005066.
PTM databases
PhosphoSite	P31938.
2D gel databases
UCD-2DPAGE	P31938.
Proteomic databases
PaxDb	P31938.
PRIDE	P31938.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000005066; ENSMUSP00000005066; ENSMUSG00000004936.
GeneID	26395.
KEGG	mmu:26395.
Organism-specific databases
CTD	5604.
MGI	MGI:1346866. Map2k1.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000234206.
HOVERGEN	HBG108518.
InParanoid	P31938.
KO	K04368.
OMA	ELMFGCP.
OrthoDB	EOG4SF965.
Enzyme and pathway databases
BRENDA	2.7.12.2. 3474.
Reactome	REACT_107772. Immune System.
Gene expression databases
ArrayExpress	P31938.
Bgee	P31938.
CleanEx	MM_MAP2K1.
Genevestigator	P31938.
GermOnline	ENSMUSG00000004936. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P31938.
ChEMBL	CHEMBL5860.
ChiTaRS	MAP2K1. mouse.
NextBio	304339.
SOURCE	Search...

Entry information

Entry name

MP2K1_MOUSE

Accession

Primary (citable) accession number: P31938

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 133 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program