UniProt Accession

 MP2K1_HUMAN; Q02750 

Genbank Protein ID

 L05624; L11284 

Genbank Nucleotide ID

 AAA36318.1 

Protein Name

 Dual specificity mitogen-activated protein kinase kinase 1 

Protein Synonyms/Alias

 MAP kinase kinase 1; MAPKK 1; MKK1; ERK activator kinase 1; MAPK/ERK kinase 1; MEK 1 

Gene Name

 MAP2K1 

Gene Synonyms/Alias

 MEK1; PRKMK1 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
36	NLEALQKKLEELELD	ubiquitination	[1, 2]
57	LEAFLTQKQKVGELK	ubiquitination	[1, 2]
64	KQKVGELKDDDFEKI	acetylation	[3]
64	KQKVGELKDDDFEKI	ubiquitination	[1]
104	KLIHLEIKPAIRNQI	sumoylation	[4]
168	IPEQILGKVSIAVIK	ubiquitination	[5]
175	KVSIAVIKGLTYLRE	ubiquitination	[2, 6]
192	KIMHRDVKPSNILVN	ubiquitination	[1]
353	PAERADLKQLMVHAF	ubiquitination	[6]

Reference

 [1] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3.
 Sol EM, Wagner SA, Weinert BT, Kumar A, Kim HS, Deng CX, Choudhary C.
 PLoS One. 2012;7(12):e50545. [PMID: 23236377]
 [4] Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation.
 Kubota Y, O'Grady P, Saito H, Takekawa M.
 Nat Cell Biol. 2011 Mar;13(3):282-91. [PMID: 21336309]
 [5] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [6] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473] 

Functional Description

 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. 

Sequence Annotation

 DOMAIN 68 361 Protein kinase.
 NP_BIND 74 82 ATP.
 NP_BIND 143 146 ATP.
 NP_BIND 150 153 ATP.
 NP_BIND 192 195 ATP.
 REGION 77 78 Inhibitor binding.
 REGION 144 146 Inhibitor binding.
 REGION 208 212 Inhibitor binding.
 REGION 270 307 RAF1-binding (By similarity).
 ACT_SITE 190 190 Proton acceptor (By similarity).
 BINDING 77 77 Inhibitor; via carbonyl oxygen.
 BINDING 78 78 Inhibitor; via amide nitrogen and
 BINDING 97 97 ATP.
 BINDING 97 97 Inhibitor.
 BINDING 190 190 Inhibitor.
 BINDING 194 194 Inhibitor; via carbonyl oxygen.
 BINDING 208 208 ATP.
 BINDING 208 208 Inhibitor.
 BINDING 212 212 Inhibitor; via amide nitrogen.
 MOD_RES 218 218 Phosphoserine; by RAF.
 MOD_RES 222 222 Phosphoserine; by RAF.
 MOD_RES 286 286 Phosphothreonine.
 MOD_RES 292 292 Phosphothreonine; by MAPK1 (By
 MOD_RES 298 298 Phosphoserine; by PAK.  

Keyword

 3D-structure; Acetylation; Alternative splicing; ATP-binding; Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing; Disease mutation; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 393 AA 

Protein Sequence

Gene Ontology

 GO:0005938; C:cell cortex; IEA:Compara.
 GO:0005829; C:cytosol; TAS:UniProtKB.
 GO:0032839; C:dendrite cytoplasm; IEA:Compara.
 GO:0005769; C:early endosome; TAS:UniProtKB.
 GO:0005925; C:focal adhesion; TAS:UniProtKB.
 GO:0005794; C:Golgi apparatus; TAS:UniProtKB.
 GO:0005770; C:late endosome; TAS:UniProtKB.
 GO:0005739; C:mitochondrion; TAS:UniProtKB.
 GO:0005634; C:nucleus; TAS:UniProtKB.
 GO:0043204; C:perikaryon; IEA:Compara.
 GO:0048471; C:perinuclear region of cytoplasm; IEA:Compara.
 GO:0005886; C:plasma membrane; IDA:HPA.
 GO:0005816; C:spindle pole body; IEA:UniProtKB-SubCell.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004708; F:MAP kinase kinase activity; IDA:UniProtKB.
 GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
 GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome.
 GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
 GO:0004728; F:receptor signaling protein tyrosine phosphatase activity; IEA:Compara.
 GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
 GO:0007411; P:axon guidance; TAS:Reactome.
 GO:0007050; P:cell cycle arrest; IMP:BHF-UCL.
 GO:0048870; P:cell motility; IEA:Compara.
 GO:0008283; P:cell proliferation; IEA:Compara.
 GO:0006928; P:cellular component movement; TAS:ProtInc.
 GO:0090398; P:cellular senescence; IMP:BHF-UCL.
 GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
 GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
 GO:0048313; P:Golgi inheritance; IEA:Compara.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
 GO:0030216; P:keratinocyte differentiation; IEA:Compara.
 GO:0060711; P:labyrinthine layer development; IEA:Compara.
 GO:0032402; P:melanosome transport; IEA:Compara.
 GO:0007067; P:mitosis; IEA:Compara.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
 GO:0034111; P:negative regulation of homotypic cell-cell adhesion; IEA:Compara.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0060674; P:placenta blood vessel development; IEA:Compara.
 GO:0045597; P:positive regulation of cell differentiation; IEA:Compara.
 GO:0030335; P:positive regulation of cell migration; IEA:Compara.
 GO:0032320; P:positive regulation of Ras GTPase activity; IEA:Compara.
 GO:0046579; P:positive regulation of Ras protein signal transduction; IEA:Compara.
 GO:0032968; P:positive regulation of transcription elongation from RNA polymerase II promoter; IEA:Compara.
 GO:0051291; P:protein heterooligomerization; IEA:Compara.
 GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
 GO:2000641; P:regulation of early endosome to late endosome transport; TAS:UniProtKB.
 GO:0090170; P:regulation of Golgi inheritance; TAS:UniProtKB.
 GO:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB.
 GO:0003056; P:regulation of vascular smooth muscle contraction; IEA:Compara.
 GO:0048678; P:response to axon injury; IEA:Compara.
 GO:0051384; P:response to glucocorticoid stimulus; IEA:Compara.
 GO:0006979; P:response to oxidative stress; IEA:Compara.
 GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
 GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
 GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
 GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
 GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0047496; P:vesicle transport along microtubule; IEA:Compara. 

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. 

Pfam

 PF00069; Pkinase 

SMART

 SM00220; S_TKc 

PROSITE

 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS