UniProt Accession

 MP2K6_HUMAN; P52564 

Genbank Protein ID

 U39657; U39656; U49732; U39065; U39064; D87905; X96757; BC012009 

Genbank Nucleotide ID

 AAC50389.1; AAC50388.1; AAB05035.1; AAB03705.1; AAB03708.1; BAA13496.1; CAA65532.1; AAH12009.1 

Protein Name

 Dual specificity mitogen-activated protein kinase kinase 6 

Protein Synonyms/Alias

 MAP kinase kinase 6; MAPKK 6; MAPK/ERK kinase 6; MEK 6; Stress-activated protein kinase kinase 3; SAPK kinase 3; SAPKK-3; SAPKK3 

Gene Name

 MAP2K6 

Gene Synonyms/Alias

 MEK6; MKK6; PRKMK6; SKK3 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
69	GAYGVVEKMRHVPSG	ubiquitination	[1]
172	ALEHLHSKLSVIHRD	acetylation	[2]
172	ALEHLHSKLSVIHRD	ubiquitination	[1]
210	YLVDSVAKTIDAGCK	acetylation	[2]
232	INPELNQKGYSVKSD	ubiquitination	[1]

Reference

 [1] 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]
 [2] VopA inhibits ATP binding by acetylating the catalytic loop of MAPK kinases.
 Trosky JE, Li Y, Mukherjee S, Keitany G, Ball H, Orth K.
 J Biol Chem. 2007 Nov 23;282(47):34299-305. [PMID: 17881352] 

Functional Description

 Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG- dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases. 

Sequence Annotation

 DOMAIN 53 314 Protein kinase.
 NP_BIND 59 67 ATP (By similarity).
 REGION 4 19 D domain (By similarity).
 REGION 311 334 DVD domain.
 ACT_SITE 179 179 Proton acceptor (By similarity).
 BINDING 82 82 ATP (By similarity).
 MOD_RES 207 207 O-acetylserine; by Yersinia yopJ;
 MOD_RES 207 207 Phosphoserine; by MAP3K; alternate.
 MOD_RES 211 211 O-acetylthreonine; by Yersinia yopJ;
 MOD_RES 211 211 Phosphothreonine; by MAP3K; alternate.  

Keyword

 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; Complete proteome; Cytoplasm; Cytoskeleton; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; Stress response; Transcription; Transcription regulation; Transferase; Tyrosine-protein kinase. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 334 AA 

Protein Sequence

Gene Ontology

 GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005654; C:nucleoplasm; TAS:Reactome.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004708; F:MAP kinase kinase activity; TAS:ProtInc.
 GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
 GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
 GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO:0007050; P:cell cycle arrest; TAS:ProtInc.
 GO:0006975; P:DNA damage induced protein phosphorylation; TAS:ProtInc.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0042692; P:muscle cell differentiation; TAS:Reactome.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
 GO:0051149; P:positive regulation of muscle cell differentiation; TAS:Reactome.
 GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
 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:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. 

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