Q01986 (MP2K1_RAT) 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

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

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 Ref.12
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.6 Ref.7 Ref.10 Ref.11
Subunit structure	Forms a heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with MORG1 and VRK2 By similarity. Found in a complex with at least BRAF, HRAS1, MAP2K1, MAPK3/ERK1 and RGS14. Interacts with ARRB2, LAMTOR3, MAPK1/ERK2, and RAF1 (via the proline-rich domain). Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity. Ref.6 Ref.7 Ref.9 Ref.11 Ref.13
Subcellular location	Cytoplasm › cytoskeleton › centrosome. Cytoplasm › cytoskeleton › spindle pole body. Cytoplasm. Nucleus. Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis.
Domain	The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1. Ref.6
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.8 Ref.10 Ref.11
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 mutant phenotype PubMed 9458043. Source: RGD cell cycle arrest Inferred from electronic annotation. Source: Compara cell motility Inferred from electronic annotation. Source: Compara cell proliferation Inferred from direct assay PubMed 16481589. Source: RGD cellular senescence Inferred from electronic annotation. Source: Compara keratinocyte differentiation Inferred from electronic annotation. Source: Compara labyrinthine layer development Inferred from electronic annotation. Source: Compara melanosome transport Inferred from direct assay PubMed 15753041. Source: RGD mitosis Inferred from direct assay PubMed 12695496. Source: RGD negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of homotypic cell-cell adhesion Inferred from mutant phenotype PubMed 17183546. Source: RGD neuron projection morphogenesis Inferred from mutant phenotype PubMed 17202850. Source: RGD placenta blood vessel development Inferred from electronic annotation. Source: Compara positive regulation of Ras GTPase activity Inferred from mutant phenotype PubMed 17183546. Source: RGD positive regulation of Ras protein signal transduction Inferred from mutant phenotype PubMed 19029245. Source: MGI positive regulation of cell differentiation Inferred from electronic annotation. Source: Compara positive regulation of cell migration Inferred from mutant phenotype PubMed 17183546. Source: RGD positive regulation of transcription elongation from RNA polymerase II promoter Inferred from mutant phenotype PubMed 18086894. Source: RGD protein heterooligomerization Inferred from physical interaction PubMed 15917294. Source: RGD regulation of Golgi inheritance Traceable author statement Ref.16. Source: UniProtKB regulation of early endosome to late endosome transport Traceable author statement Ref.16. Source: UniProtKB regulation of stress-activated MAPK cascade Traceable author statement Ref.16. Source: UniProtKB regulation of vascular smooth muscle contraction Inferred from mutant phenotype PubMed 10198244. Source: RGD response to axon injury Inferred from mutant phenotype PubMed 15737734. Source: RGD response to glucocorticoid stimulus Inferred from direct assay PubMed 11872750. Source: RGD response to oxidative stress Inferred from direct assay PubMed 16481589. Source: RGD vesicle transport along microtubule Inferred from direct assay PubMed 15753041. Source: RGD
Cellular_component	Golgi apparatus Traceable author statement Ref.16. Source: UniProtKB axon part Inferred from direct assay PubMed 9714150. Source: RGD cell cortex Inferred from direct assay PubMed 16272159. Source: RGD cytosol Traceable author statement Ref.16. Source: UniProtKB dendrite cytoplasm Inferred from direct assay PubMed 9714150. Source: RGD early endosome Traceable author statement Ref.16. Source: UniProtKB focal adhesion Traceable author statement Ref.16. Source: UniProtKB late endosome Traceable author statement Ref.16. Source: UniProtKB mitochondrion Traceable author statement Ref.16. Source: UniProtKB nucleus Traceable author statement Ref.16. Source: UniProtKB perikaryon Inferred from direct assay PubMed 10465442PubMed 9714150. Source: RGD perinuclear region of cytoplasm Inferred from direct assay Ref.10. Source: RGD plasma membrane Inferred from direct assay Ref.10. Source: RGD spindle pole body Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from direct assay PubMed 7611406. Source: RGD MAP kinase kinase activity Inferred from direct assay PubMed 7611406PubMed 7624324PubMed 7935430PubMed 8393135. Source: RGD mitogen-activated protein kinase kinase kinase binding Inferred from direct assay Ref.6. Source: RGD 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 electronic annotation. Source: Compara
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_0000086369
Regions
	Domain	68 – 361	294	Protein kinase
	Nucleotide binding	74 – 82	9	ATP By similarity
	Region	270 – 307	38	RAF1-binding
	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 Ref.11
	Modified residue	298	1	Phosphoserine; by PAK Ref.10 Ref.11

Sequences

	Sequence		Length	Mass (Da)
	Q01986 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: A1C8D18FFC852D51	FASTA	393	43,465
	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 LELLFGCQVE 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]	"Molecular structure of a protein-tyrosine/threonine kinase activating p42 mitogen-activated protein (MAP) kinase: MAP kinase kinase." Wu J., Harrison J.K., Vincent L.A., Haystead C., Haystead T.A.J., Michel H., Hunt D.F., Lynch K.R., Sturgill T.W. Proc. Natl. Acad. Sci. U.S.A. 90:173-177(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Kidney.
[2]	"Isolation of two members of the rat MAP kinase kinase gene family." Otsu M., Terada Y., Okayama H. FEBS Lett. 320:246-250(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Cloning and sequencing of a cDNA encoding rat brain mitogen-activated protein (MAP) kinase activator." Doering F., Drewes G., Berling B., Mandelkow E.M. Gene 131:303-304(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Strain: Sprague-Dawley.
[4]	"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]. Tissue: Thymus.
[5]	Lubec G., Chen W.-Q. Submitted (APR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 206-227; 270-291 AND 325-340, MASS SPECTROMETRY. Strain: Sprague-Dawley. Tissue: Hippocampus.
[6]	"A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function." Catling A.D., Schaeffer H.J., Reuter C.W., Reddy G.R., Weber M.J. Mol. Cell. Biol. 15:5214-5225(1995) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN, INTERACTION WITH RAF1, ENZYME REGULATION.
[7]	"MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade." Schaeffer H.J., Catling A.D., Eblen S.T., Collier L.S., Krauss A., Weber M.J. Science 281:1668-1671(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LAMTOR3, ENZYME REGULATION.
[8]	"A specific activation of the mitogen-activated protein kinase kinase 1 (MEK1) is required for Golgi fragmentation during mitosis." Colanzi A., Deerinck T.J., Ellisman M.H., Malhotra V. J. Cell Biol. 149:331-339(2000) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, FUNCTION.
[9]	"Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds." Luttrell L.M., Roudabush F.L., Choy E.W., Miller W.E., Field M.E., Pierce K.L., Lefkowitz R.J. Proc. Natl. Acad. Sci. U.S.A. 98:2449-2454(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ARRB2.
[10]	"PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation." Slack-Davis J.K., Eblen S.T., Zecevic M., Boerner S.A., Tarcsafalvi A., Diaz H.B., Marshall M.S., Weber M.J., Parsons J.T., Catling A.D. J. Cell Biol. 162:281-291(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-298, ENZYME REGULATION.
[11]	"Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion." Eblen S.T., Slack-Davis J.K., Tarcsafalvi A., Parsons J.T., Weber M.J., Catling A.D. Mol. Cell. Biol. 24:2308-2317(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-292 AND SER-298, INTERACTION WITH MAPK1/ERK2, ENZYME REGULATION.
[12]	"The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes." Nada S., Hondo A., Kasai A., Koike M., Saito K., Uchiyama Y., Okada M. EMBO J. 28:477-489(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION OF THE MAPK/ERK PATHWAY.
[13]	"Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector." Willard F.S., Willard M.D., Kimple A.J., Soundararajan M., Oestreich E.A., Li X., Sowa N.A., Kimple R.J., Doyle D.A., Der C.J., Zylka M.J., Snider W.D., Siderovski D.P. PLoS ONE 4:E4884-E4884(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS1; MAPK3 AND RGS14.
[14]	"Signaling by dual specificity kinases." Dhanasekaran N., Premkumar Reddy E. Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[15]	"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.
[16]	"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.
[17]	"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	Z16415 mRNA. Translation: CAA78905.1. D13341 mRNA. Translation: BAA02603.1. D14591 mRNA. Translation: BAA03441.1. X62313 mRNA. Translation: CAA44192.1. BC089772 mRNA. Translation: AAH89772.1.
IPI	IPI00231247.
PIR	JN0840.
RefSeq	NP_113831.1. NM_031643.4.
UniGene	Rn.5850.
3D structure databases
ProteinModelPortal	Q01986.
SMR	Q01986. Positions 62-382.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000013933.
PTM databases
PhosphoSite	Q01986.
Proteomic databases
PaxDb	Q01986.
PRIDE	Q01986.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000013933; ENSRNOP00000013933; ENSRNOG00000010176.
GeneID	170851.
KEGG	rno:170851.
UCSC	RGD:70495. rat.
Organism-specific databases
CTD	5604.
RGD	70495. Map2k1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00690000101918.
HOGENOM	HOG000234206.
HOVERGEN	HBG108518.
InParanoid	Q01986.
KO	K04368.
OMA	ELMFGCP.
OrthoDB	EOG4SF965.
Enzyme and pathway databases
BRENDA	2.7.12.2. 5301.
Reactome	REACT_109781. Immune System. REACT_110573. Disease. REACT_111984. Signal Transduction. REACT_96538. Developmental Biology.
Gene expression databases
Genevestigator	Q01986.
GermOnline	ENSRNOG00000010176. Rattus norvegicus.
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
NextBio	621291.

Entry information

Entry name

MP2K1_RAT

Accession

Primary (citable) accession number: Q01986
Secondary accession number(s): Q5EBD5

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 121 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program