CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-007766
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Dual specificity mitogen-activated protein kinase kinase 4 
Protein Synonyms/Alias
 MAP kinase kinase 4; MAPKK 4; JNK-activating kinase 1; MAPK/ERK kinase 4; MEK 4; SAPK/ERK kinase 1; SEK1; Stress-activated protein kinase kinase 1; SAPK kinase 1; SAPKK-1; SAPKK1; c-Jun N-terminal kinase kinase 1; JNKK 
Gene Name
 MAP2K4 
Gene Synonyms/Alias
 JNKK1; MEK4; MKK4; PRKMK4; SEK1; SERK1; SKK1 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
131SGQIMAVKRIRSTVDacetylation[1]
231KIIHRDIKPSNILLDubiquitination[2]
Reference
 [1] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [2] 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] 
Functional Description
 Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. 
Sequence Annotation
 DOMAIN 102 367 Protein kinase.
 NP_BIND 108 116 ATP (By similarity).
 REGION 37 52 D domain.
 REGION 364 387 DVD domain.
 ACT_SITE 229 229 Proton acceptor (By similarity).
 BINDING 131 131 ATP (By similarity).
 MOD_RES 2 2 N-acetylalanine.
 MOD_RES 90 90 Phosphoserine.
 MOD_RES 257 257 Phosphoserine; by MAP3K.
 MOD_RES 261 261 Phosphothreonine; by MAP3K.  
Keyword
 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; Complete proteome; Cytoplasm; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Serine/threonine-protein kinase; Stress response; Transferase; Tyrosine-protein kinase. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 399 AA 
Protein Sequence
MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN PPFKSTARFT 60
LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE DLKDLGEIGR GAYGSVNKMV 120
HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD VVMRSSDCPY IVQFYGALFR EGDCWICMEL 180
MSTSFDKFYK YVYSVLDDVI PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS 240
GNIKLCDFGI SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL 300
ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK DESKRPKYKE 360
LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD 399 
Gene Ontology
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004672; F:protein 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:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0007254; P:JNK cascade; TAS:Reactome.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; 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. 
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