Q02750 (MP2K1_HUMAN) 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
Short name=MKK1
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

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

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.6 Ref.9
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 By similarity. Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766.
Subunit structure	Found in a complex with at least BRAF, HRAS1, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms a heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with ARBB2, LAMTOR3, MAPK1/ERK2, MORG1 and RAF1 By similarity. Interacts with PPARG and with isoform 1 of VRK2. Interacts with Yersinia yopJ. Interacts with SGK1. Interacts with BIRC6/bruce. Ref.8 Ref.9 Ref.10 Ref.12 Ref.14
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. Ref.6 Ref.9
Tissue specificity	Widely expressed, with extremely low levels in brain. Ref.1
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.3 Ref.7 Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Involvement in disease	Cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]: Characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note: The disease is caused by mutations affecting the gene represented in this entry.
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
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Golgi inheritance Inferred from electronic annotation. Source: Compara MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Ras protein signal transduction Traceable author statement. Source: Reactome TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome activation of MAPKK activity Traceable author statement. Source: Reactome axon guidance Traceable author statement. Source: Reactome cell cycle arrest Inferred from mutant phenotype PubMed 9765203. Source: BHF-UCL cell motility Inferred from electronic annotation. Source: Compara cell proliferation Inferred from electronic annotation. Source: Compara cellular component movement Traceable author statement PubMed 10912793. Source: ProtInc cellular senescence Inferred from mutant phenotype PubMed 9765203. Source: BHF-UCL epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome innate immune response Traceable author statement. Source: Reactome insulin receptor signaling pathway Traceable author statement. Source: Reactome keratinocyte differentiation Inferred from electronic annotation. Source: Compara labyrinthine layer development Inferred from electronic annotation. Source: Compara melanosome transport Inferred from electronic annotation. Source: Compara mitosis Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from direct assay PubMed 9765203. Source: BHF-UCL negative regulation of homotypic cell-cell adhesion Inferred from electronic annotation. Source: Compara nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome placenta blood vessel development Inferred from electronic annotation. Source: Compara positive regulation of Ras GTPase activity Inferred from electronic annotation. Source: Compara positive regulation of Ras protein signal transduction Inferred from electronic annotation. Source: Compara positive regulation of cell differentiation Inferred from electronic annotation. Source: Compara 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.17. Source: UniProtKB regulation of early endosome to late endosome transport Traceable author statement Ref.17. Source: UniProtKB regulation of stress-activated MAPK cascade Traceable author statement Ref.17. 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 stress-activated MAPK cascade Traceable author statement. Source: Reactome toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome vesicle transport along microtubule Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi apparatus Traceable author statement Ref.17. Source: UniProtKB axon part Inferred from electronic annotation. Source: Compara cell cortex Inferred from electronic annotation. Source: Compara cytosol Traceable author statement Ref.17. Source: UniProtKB dendrite cytoplasm Inferred from electronic annotation. Source: Compara early endosome Traceable author statement Ref.17. Source: UniProtKB focal adhesion Traceable author statement Ref.17. Source: UniProtKB late endosome Traceable author statement Ref.17. Source: UniProtKB mitochondrion Traceable author statement Ref.17. Source: UniProtKB nucleus Traceable author statement Ref.17. Source: UniProtKB perikaryon Inferred from electronic annotation. Source: Compara perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara plasma membrane Inferred from direct assay. Source: HPA 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 direct assay Ref.2. Source: UniProtKB protein serine/threonine kinase activator activity Inferred from direct assay Ref.2. Source: UniProtKB protein serine/threonine kinase activity Traceable author statement. Source: Reactome 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...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BIRC6	Q9NR09	2	EBI-492564,EBI-1765160
RAF1	P04049	2	EBI-492564,EBI-365996
VRK2	Q86Y07	2	EBI-492564,EBI-1207615
VRK2	Q86Y07-1	2	EBI-492564,EBI-1207633

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q02750-1)

Also known as: MKK1a;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q02750-2)

Also known as: MKK1b;

The sequence of this isoform differs from the canonical sequence as follows:
     147-172: Missing.

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_0000086365

Regions

Domain

68 – 361

294

Protein kinase

Nucleotide binding

74 – 82

9

ATP

Nucleotide binding

143 – 146

4

ATP

Nucleotide binding

150 – 153

4

ATP

Nucleotide binding

192 – 195

4

ATP

Region

77 – 78

2

Inhibitor binding

Region

144 – 146

3

Inhibitor binding

Region

208 – 212

5

Inhibitor binding

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

77

1

Inhibitor; via carbonyl oxygen

Binding site

78

1

Inhibitor; via amide nitrogen and carbonyl oxygen

Binding site

97

1

ATP

Binding site

97

1

Inhibitor

Binding site

190

1

Inhibitor

Binding site

194

1

Inhibitor; via carbonyl oxygen

Binding site

208

1

ATP

Binding site

208

1

Inhibitor

Binding site

212

1

Inhibitor; via amide nitrogen

Site

8 – 9

2

Cleavage; by anthrax lethal factor

Amino acid modifications

Modified residue

218

1

Phosphoserine; by RAF Ref.3

Modified residue

222

1

Phosphoserine; by RAF Ref.3

Modified residue

286

1

Phosphothreonine Ref.11

Modified residue

292

1

Phosphothreonine; by MAPK1 By similarity

Modified residue

298

1

Phosphoserine; by PAK Ref.7

Natural variations

Alternative sequence

147 – 172

26

Missing in isoform 2.

VSP_040500

Natural variant

53

1

F → S in CFC syndrome. Ref.29

VAR_035093

Natural variant

130

1

Y → C in CFC syndrome. Ref.29

VAR_035094

Experimental info

Mutagenesis

97

1

K → R: Inactivation.

Mutagenesis

150

1

S → A: No loss of activity.

Mutagenesis

212

1

S → A: No loss of activity.

Mutagenesis

218

1

S → A: Inactivation.

Mutagenesis

222

1

S → A: Inactivation.

Secondary structure

1

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393

Helix Strand Turn

Details...

Helix

44 – 58

15

Helix

65 – 67

3

Beta strand

68 – 76

9

Beta strand

81 – 87

7

Turn

88 – 90

3

Beta strand

93 – 100

8

Helix

105 – 115

11

Helix

116 – 120

5

Beta strand

129 – 135

7

Beta strand

138 – 143

6

Helix

151 – 158

8

Helix

163 – 184

22

Helix

193 – 195

3

Beta strand

196 – 198

3

Turn

200 – 202

3

Beta strand

204 – 206

3

Helix

213 – 218

6

Turn

220 – 222

3

Helix

227 – 229

3

Helix

232 – 235

4

Helix

242 – 258

17

Helix

268 – 275

8

Helix

310 – 319

10

Turn

327 – 329

3

Helix

332 – 342

11

Turn

346 – 348

3

Helix

352 – 356

5

Helix

359 – 366

8

Helix

371 – 379

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (MKK1a) [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 0344118FFC842D51	FASTA	393	43,439
	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 LELMFGCQVE GDAAETPPRP RTPGRPLSSY 310 320 330 340 350 360 GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF 370 380 390 IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV
	Isoform 2 (MKK1b) [UniParc]. Checksum: 9944432D8705DEFD	FASTA	367	40,764
	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 ICMEHMVIKG LTYLREKHKI MHRDVKPSNI LVNSRGEIKL 190 200 210 220 230 240 CDFGVSGQLI DSMANSFVGT RSYMSPERLQ GTHYSVQSDI WSMGLSLVEM AVGRYPIPPP 250 260 270 280 290 300 DAKELELMFG CQVEGDAAET PPRPRTPGRP LSSYGMDSRP PMAIFELLDY IVNEPPPKLP 310 320 330 340 350 360 SGVFSLEFQD FVNKCLIKNP AERADLKQLM VHAFIKRSDA EEVDFAGWLC STIGLNQPST PTHAAGV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases." Seger R., Seger D., Lozeman F.J., Ahn N.G., Graves L.M., Campbell J.S., Ericsson L., Harrylock M., Jensen A.M., Krebs E.G. J. Biol. Chem. 267:25628-25631(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), PARTIAL PROTEIN SEQUENCE, TISSUE SPECIFICITY. Tissue: T-cell.
[2]	"Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2." Zheng C.-F., Guan K.-L. J. Biol. Chem. 268:11435-11439(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues." Zheng C.-F., Guan K.-L. EMBO J. 13:1123-1131(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-218 AND SER-222, MUTAGENESIS.
[4]	"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, PROTEIN SEQUENCE OF 9-17.
[5]	"Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor." Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C. Biochem. J. 352:739-745(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[6]	"The MAP kinase pathway is required for entry into mitosis and cell survival." Liu X., Yan S., Zhou T., Terada Y., Erikson R.L. Oncogene 23:763-776(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, FUNCTION.
[7]	"Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors." Beeser A., Jaffer Z.M., Hofmann C., Chernoff J. J. Biol. Chem. 280:36609-36615(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-298.
[8]	"Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation." Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., Orth K. Science 312:1211-1214(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH YOPJ, ACETYLATION.
[9]	"Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor gamma." Burgermeister E., Chuderland D., Hanoch T., Meyer M., Liscovitch M., Seger R. Mol. Cell. Biol. 27:803-817(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PPARG.
[10]	"Final stages of cytokinesis and midbody ring formation are controlled by BRUCE." Pohl C., Jentsch S. Cell 132:832-845(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH BIRC6/BRUCE.
[11]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-286, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration." Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J., Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M., Hur G.M. J. Hepatol. 51:67-76(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SGK1.
[13]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]	"VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer." Fernandez I.F., Blanco S., Lozano J., Lazo P.A. Mol. Cell. Biol. 30:4687-4697(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH VRK2.
[15]	"Signaling by dual specificity kinases." Dhanasekaran N., Premkumar Reddy E. Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[16]	"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.
[17]	"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.
[18]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[19]	"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.
[20]	"Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition." Ohren J.F., Chen H., Pavlovsky A., Whitehead C., Zhang E., Kuffa P., Yan C., McConnell P., Spessard C., Banotai C., Mueller W.T., Delaney A., Omer C., Sebolt-Leopold J., Dudley D.T., Leung I.K., Flamme C., Warmus J. , Kaufman M., Barrett S., Tecle H., Hasemann C.A. Nat. Struct. Mol. Biol. 11:1192-1197(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 62-392 IN COMPLEX WITH ATP AND INHIBITOR.
[21]	"4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase." Spicer J.A., Rewcastle G.W., Kaufman M.D., Black S.L., Plummer M.S., Denny W.A., Quin J. III, Shahripour A.B., Barrett S.D., Whitehead C.E., Milbank J.B., Ohren J.F., Gowan R.C., Omer C., Camp H.S., Esmaeil N., Moore K., Sebolt-Leopold J.S. , Pryzbranowski S., Merriman R.L., Ortwine D.F., Warmus J.S., Flamme C.M., Pavlovsky A.G., Tecle H. J. Med. Chem. 50:5090-5102(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND INHIBITOR.
[22]	"2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)." Warmus J.S., Flamme C., Zhang L.Y., Barrett S., Bridges A., Chen H., Gowan R., Kaufman M., Sebolt-Leopold J., Leopold W., Merriman R., Ohren J., Pavlovsky A., Przybranowski S., Tecle H., Valik H., Whitehead C., Zhang E. Bioorg. Med. Chem. Lett. 18:6171-6174(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND INHIBITOR.
[23]	"Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors." Fischmann T.O., Smith C.K., Mayhood T.W., Myers J.E., Reichert P., Mannarino A., Carr D., Zhu H., Wong J., Yang R.S., Le H.V., Madison V.S. Biochemistry 48:2661-2674(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 35-393 IN COMPLEX WITH ADP AND INHIBITOR.
[24]	"Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?" Tecle H., Shao J., Li Y., Kothe M., Kazmirski S., Penzotti J., Ding Y.H., Ohren J., Moshinsky D., Coli R., Jhawar N., Bora E., Jacques-O'Hagan S., Wu J. Bioorg. Med. Chem. Lett. 19:226-229(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP AND INHIBITOR.
[25]	"RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer." Iverson C., Larson G., Lai C., Yeh L.T., Dadson C., Weingarten P., Appleby T., Vo T., Maderna A., Vernier J.M., Hamatake R., Miner J.N., Quart B. Cancer Res. 69:6839-6847(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND INHIBITOR.
[26]	"Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors." Wallace M.B., Adams M.E., Kanouni T., Mol C.D., Dougan D.R., Feher V.A., O'Connell S.M., Shi L., Halkowycz P., Dong Q. Bioorg. Med. Chem. Lett. 20:4156-4158(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 62-382 IN COMPLEX WITH ADP AND INHIBITOR.
[27]	"Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer." Dong Q., Dougan D.R., Gong X., Halkowycz P., Jin B., Kanouni T., O'Connell S.M., Scorah N., Shi L., Wallace M.B., Zhou F. Bioorg. Med. Chem. Lett. 21:1315-1319(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP AND INHIBITOR.
[28]	"Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent." Isshiki Y., Kohchi Y., Iikura H., Matsubara Y., Asoh K., Murata T., Kohchi M., Mizuguchi E., Tsujii S., Hattori K., Miura T., Yoshimura Y., Aida S., Miwa M., Saitoh R., Murao N., Okabe H., Belunis C. , Janson C., Lukacs C., Schuck V., Shimma N. Bioorg. Med. Chem. Lett. 21:1795-1801(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393.
[29]	"Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome." Rodriguez-Viciana P., Tetsu O., Tidyman W.E., Estep A.L., Conger B.A., Cruz M.S., McCormick F., Rauen K.A. Science 311:1287-1290(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CFC SYNDROME SER-53 AND CYS-130.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L05624 mRNA. Translation: AAA36318.1.
L11284 mRNA. No translation available.

IPI

IPI00219604.
IPI00797850.

PIR

A45100.

RefSeq

NP_002746.1. NM_002755.3.

UniGene

Hs.145442.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1S9J	X-ray	2.40	A	62-392	[»]
2P55	X-ray	2.80	A	62-393	[»]
3DV3	X-ray	2.30	A	62-382	[»]
3DY7	X-ray	2.70	A	62-393	[»]
3E8N	X-ray	2.50	A	62-393	[»]
3EQB	X-ray	2.62	A	62-393	[»]
3EQC	X-ray	1.80	A	35-393	[»]
3EQD	X-ray	2.10	A	35-393	[»]
3EQF	X-ray	2.70	A	35-393	[»]
3EQG	X-ray	2.50	A	35-393	[»]
3EQH	X-ray	2.00	A	35-393	[»]
3EQI	X-ray	1.90	A	35-393	[»]
3MBL	X-ray	2.60	A	62-382	[»]
3ORN	X-ray	2.80	A	62-393	[»]
3OS3	X-ray	2.80	A	62-393	[»]
3PP1	X-ray	2.70	A	62-382	[»]
3SLS	X-ray	2.30	A/B	45-383	[»]
3V01	X-ray	2.70	A	62-393	[»]
3V04	X-ray	2.70	A	62-393	[»]
4AN2	X-ray	2.50	A	61-392	[»]
4AN3	X-ray	2.10	A	61-392	[»]
4AN9	X-ray	2.80	A	61-392	[»]
4ANB	X-ray	2.20	A	61-392	[»]
4ARK	X-ray	2.60	A	62-393	[»]

ProteinModelPortal

Q02750.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-201N.

IntAct

Q02750. 19 interactions.

MINT

MINT-99632.

STRING

9606.ENSP00000302486.

PTM databases

PhosphoSite

Q02750.

Polymorphism databases

DMDM

400274.

Proteomic databases

PaxDb

Q02750.

PeptideAtlas

Q02750.

PRIDE

Q02750.

Protocols and materials databases

DNASU

5604.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000307102; ENSP00000302486; ENSG00000169032.

GeneID

5604.

KEGG

hsa:5604.

UCSC

uc010bhq.3. human.

Organism-specific databases

CTD

5604.

GeneCards

GC15P066679.

HGNC

HGNC:6840. MAP2K1.

HPA

CAB003834.
HPA026430.

MIM

115150. phenotype.
176872. gene.

neXtProt

NX_Q02750.

Orphanet

1340. Cardiofaciocutaneous syndrome.

PharmGKB

PA30584.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000234206.

HOVERGEN

HBG108518.

InParanoid

Q02750.

KO

K04368.

OMA

ELMFGCP.

OrthoDB

EOG4SF965.

PhylomeDB

Q02750.

Enzyme and pathway databases

BRENDA

2.7.12.2. 2681.

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
anthraxpathway. Cellular roles of Anthrax toxin.
ceramidepathway. Ceramide signaling pathway.
pi3kcibpathway. Class IB PI3K non-lipid kinase events.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
endothelinpathway. Endothelins.
ephbfwdpathway. EPHB forward signaling.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
foxm1pathway. FOXM1 transcription factor network.
hedgehog_glipathway. Hedgehog signaling events mediated by Gli proteins.
ifngpathway. IFN-gamma pathway.
il2_1pathway. IL2-mediated signaling events.
trkrpathway. Neurotrophic factor-mediated Trk receptor signaling.
tcrraspathway. Ras signaling in the CD4+ TCR pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q02750.

Bgee

Q02750.

CleanEx

HS_MAP2K1.

Genevestigator

Q02750.

GermOnline

ENSG00000169032. Homo sapiens.

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

Q02750.

ChEMBL

CHEMBL3587.

ChiTaRS

MAP2K1. human.

EvolutionaryTrace

Q02750.

GenomeRNAi

5604.

NextBio

21776.

PMAP-CutDB

Q02750.

SOURCE

Search...

Entry information

Entry name

MP2K1_HUMAN

Accession

Primary (citable) accession number: Q02750

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 148 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.