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Protein

Dual specificity mitogen-activated protein kinase kinase 4

Gene

MAP2K4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 MAPK14.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei131ATPPROSITE-ProRule annotation1
Active sitei229Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi108 – 116ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Apoptosis, Stress response

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS00847-MONOMER.
BRENDAi2.7.12.2. 2681.
ReactomeiR-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-2871796. FCERI mediated MAPK activation.
R-HSA-450321. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
R-HSA-5210891. Uptake and function of anthrax toxins.
R-HSA-5684264. MAP3K8 (TPL2)-dependent MAPK1/3 activation.
SignaLinkiP45985.
SIGNORiP45985.

Names & Taxonomyi

Protein namesi
Recommended name:
Dual specificity mitogen-activated protein kinase kinase 4 (EC:2.7.12.2)
Short name:
MAP kinase kinase 4
Short name:
MAPKK 4
Alternative name(s):
JNK-activating kinase 1
MAPK/ERK kinase 4
Short name:
MEK 4
SAPK/ERK kinase 1
Short name:
SEK1
Stress-activated protein kinase kinase 1
Short name:
SAPK kinase 1
Short name:
SAPKK-1
Short name:
SAPKK1
c-Jun N-terminal kinase kinase 1
Short name:
JNKK
Gene namesi
Name:MAP2K4
Synonyms:JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:6844. MAP2K4.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi6416.
OpenTargetsiENSG00000065559.
PharmGKBiPA30589.

Chemistry databases

ChEMBLiCHEMBL2897.
GuidetoPHARMACOLOGYi2065.

Polymorphism and mutation databases

BioMutaiMAP2K4.
DMDMi1170596.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000863812 – 399Dual specificity mitogen-activated protein kinase kinase 4Add BLAST398

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei58Asymmetric dimethylarginine; alternateCombined sources1
Modified residuei58Omega-N-methylarginine; alternateCombined sources1
Modified residuei90PhosphoserineCombined sources1
Modified residuei257Phosphoserine; by MAP3KCombined sources1
Modified residuei261Phosphothreonine; by MAP3K1 Publication1

Post-translational modificationi

Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei45 – 46Cleavage; by anthrax lethal factor2
Sitei58 – 59Cleavage; by anthrax lethal factor2

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein

Proteomic databases

EPDiP45985.
MaxQBiP45985.
PaxDbiP45985.
PeptideAtlasiP45985.
PRIDEiP45985.

PTM databases

iPTMnetiP45985.
PhosphoSitePlusiP45985.

Miscellaneous databases

PMAP-CutDBP45985.

Expressioni

Tissue specificityi

Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.

Gene expression databases

BgeeiENSG00000065559.
CleanExiHS_MAP2K4.
ExpressionAtlasiP45985. baseline and differential.
GenevisibleiP45985. HS.

Organism-specific databases

HPAiCAB007751.

Interactioni

Subunit structurei

Interacts with SPAG9 (By similarity). Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
MAP3K1Q132333EBI-447868,EBI-49776

Protein-protein interaction databases

BioGridi112315. 41 interactors.
IntActiP45985. 16 interactors.
MINTiMINT-151438.
STRINGi9606.ENSP00000262445.

Chemistry databases

BindingDBiP45985.

Structurei

Secondary structure

1399
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi81 – 83Combined sources3
Beta strandi85 – 88Combined sources4
Beta strandi93 – 95Combined sources3
Beta strandi101 – 103Combined sources3
Beta strandi107 – 110Combined sources4
Beta strandi112 – 121Combined sources10
Turni122 – 124Combined sources3
Beta strandi127 – 134Combined sources8
Helixi139 – 153Combined sources15
Beta strandi164 – 169Combined sources6
Beta strandi171 – 178Combined sources8
Beta strandi182 – 184Combined sources3
Helixi185 – 194Combined sources10
Helixi202 – 223Combined sources22
Helixi232 – 234Combined sources3
Beta strandi235 – 237Combined sources3
Beta strandi243 – 245Combined sources3
Beta strandi249 – 251Combined sources3
Beta strandi255 – 259Combined sources5
Beta strandi267 – 270Combined sources4
Helixi272 – 274Combined sources3
Helixi287 – 302Combined sources16
Beta strandi312 – 314Combined sources3
Beta strandi316 – 321Combined sources6
Helixi338 – 347Combined sources10
Helixi352 – 354Combined sources3
Helixi358 – 361Combined sources4
Helixi365 – 372Combined sources8
Helixi377 – 387Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3ALNX-ray2.30A/B/C80-399[»]
3ALOX-ray2.60A80-399[»]
3VUTX-ray3.50A/B80-399[»]
ProteinModelPortaliP45985.
SMRiP45985.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP45985.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini102 – 367Protein kinasePROSITE-ProRule annotationAdd BLAST266

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni37 – 52D domainAdd BLAST16
Regioni364 – 387DVD domainAdd BLAST24

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi5 – 19Gly/Ser-richAdd BLAST15

Domaini

The DVD domain (residues 364-387) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation.
The D domain (residues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates.

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0984. Eukaryota.
ENOG410XT3F. LUCA.
GeneTreeiENSGT00760000119199.
HOVERGENiHBG108518.
InParanoidiP45985.
KOiK04430.
OMAiKFYKFIC.
OrthoDBiEOG091G0A9H.
PhylomeDBiP45985.
TreeFamiTF350701.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P45985-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN
60 70 80 90 100
PPFKSTARFT LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE
110 120 130 140 150
DLKDLGEIGR GAYGSVNKMV HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD
160 170 180 190 200
VVMRSSDCPY IVQFYGALFR EGDCWICMEL MSTSFDKFYK YVYSVLDDVI
210 220 230 240 250
PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS GNIKLCDFGI
260 270 280 290 300
SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL
310 320 330 340 350
ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK
360 370 380 390
DESKRPKYKE LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD
Length:399
Mass (Da):44,288
Last modified:November 1, 1995 - v1
Checksum:iA472537F2F26770B
GO
Isoform 2 (identifier: P45985-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     39-39: G → GFQINFCEKAQS

Note: No experimental confirmation available.
Show »
Length:410
Mass (Da):45,584
Checksum:i097F8966398DD6C0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti118K → R in CAG38801 (Ref. 4) Curated1
Sequence conflicti179E → G in BAG35884 (PubMed:14702039).Curated1
Sequence conflicti356P → L in AAH60764 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06296316S → R.1 PublicationCorresponds to variant rs17855590dbSNPEnsembl.1
Natural variantiVAR_040818142Q → L in a lung squamous cell carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_040819154R → W in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_040820234N → I in an ovarian serous carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_040821251S → N in a metastatic melanoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_040822279A → T in a colorectal adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant rs753665559dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_03883839G → GFQINFCEKAQS in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L36870 mRNA. Translation: AAC41719.1.
U17743 mRNA. Translation: AAC50127.1.
AF070090
, AF070080, AF070081, AF070082, AF070083, AF070084, AF070085, AF070086, AF070087, AF070088, AF070089 Genomic DNA. Translation: AAC24130.1.
CR536564 mRNA. Translation: CAG38801.1.
BT019676 mRNA. Translation: AAV38482.1.
AK131544 mRNA. Translation: BAG54774.1.
AK313053 mRNA. Translation: BAG35884.1.
DQ015703 Genomic DNA. Translation: AAY22176.1.
AC005244 Genomic DNA. No translation available.
AC005410 Genomic DNA. No translation available.
CH471108 Genomic DNA. Translation: EAW89975.1.
CH471108 Genomic DNA. Translation: EAW89974.1.
CH471108 Genomic DNA. Translation: EAW89976.1.
BC036032 mRNA. Translation: AAH36032.1.
BC060764 mRNA. Translation: AAH60764.1.
CCDSiCCDS11162.1. [P45985-1]
CCDS62095.1. [P45985-2]
PIRiI38901.
RefSeqiNP_001268364.1. NM_001281435.1. [P45985-2]
NP_003001.1. NM_003010.3. [P45985-1]
UniGeneiHs.514681.

Genome annotation databases

EnsembliENST00000353533; ENSP00000262445; ENSG00000065559. [P45985-1]
ENST00000415385; ENSP00000410402; ENSG00000065559. [P45985-2]
GeneIDi6416.
KEGGihsa:6416.
UCSCiuc002gnj.5. human. [P45985-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

NIEHS-SNPs
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L36870 mRNA. Translation: AAC41719.1.
U17743 mRNA. Translation: AAC50127.1.
AF070090
, AF070080, AF070081, AF070082, AF070083, AF070084, AF070085, AF070086, AF070087, AF070088, AF070089 Genomic DNA. Translation: AAC24130.1.
CR536564 mRNA. Translation: CAG38801.1.
BT019676 mRNA. Translation: AAV38482.1.
AK131544 mRNA. Translation: BAG54774.1.
AK313053 mRNA. Translation: BAG35884.1.
DQ015703 Genomic DNA. Translation: AAY22176.1.
AC005244 Genomic DNA. No translation available.
AC005410 Genomic DNA. No translation available.
CH471108 Genomic DNA. Translation: EAW89975.1.
CH471108 Genomic DNA. Translation: EAW89974.1.
CH471108 Genomic DNA. Translation: EAW89976.1.
BC036032 mRNA. Translation: AAH36032.1.
BC060764 mRNA. Translation: AAH60764.1.
CCDSiCCDS11162.1. [P45985-1]
CCDS62095.1. [P45985-2]
PIRiI38901.
RefSeqiNP_001268364.1. NM_001281435.1. [P45985-2]
NP_003001.1. NM_003010.3. [P45985-1]
UniGeneiHs.514681.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3ALNX-ray2.30A/B/C80-399[»]
3ALOX-ray2.60A80-399[»]
3VUTX-ray3.50A/B80-399[»]
ProteinModelPortaliP45985.
SMRiP45985.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112315. 41 interactors.
IntActiP45985. 16 interactors.
MINTiMINT-151438.
STRINGi9606.ENSP00000262445.

Chemistry databases

BindingDBiP45985.
ChEMBLiCHEMBL2897.
GuidetoPHARMACOLOGYi2065.

PTM databases

iPTMnetiP45985.
PhosphoSitePlusiP45985.

Polymorphism and mutation databases

BioMutaiMAP2K4.
DMDMi1170596.

Proteomic databases

EPDiP45985.
MaxQBiP45985.
PaxDbiP45985.
PeptideAtlasiP45985.
PRIDEiP45985.

Protocols and materials databases

DNASUi6416.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000353533; ENSP00000262445; ENSG00000065559. [P45985-1]
ENST00000415385; ENSP00000410402; ENSG00000065559. [P45985-2]
GeneIDi6416.
KEGGihsa:6416.
UCSCiuc002gnj.5. human. [P45985-1]

Organism-specific databases

CTDi6416.
DisGeNETi6416.
GeneCardsiMAP2K4.
HGNCiHGNC:6844. MAP2K4.
HPAiCAB007751.
MIMi601335. gene.
neXtProtiNX_P45985.
OpenTargetsiENSG00000065559.
PharmGKBiPA30589.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0984. Eukaryota.
ENOG410XT3F. LUCA.
GeneTreeiENSGT00760000119199.
HOVERGENiHBG108518.
InParanoidiP45985.
KOiK04430.
OMAiKFYKFIC.
OrthoDBiEOG091G0A9H.
PhylomeDBiP45985.
TreeFamiTF350701.

Enzyme and pathway databases

BioCyciZFISH:HS00847-MONOMER.
BRENDAi2.7.12.2. 2681.
ReactomeiR-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-2871796. FCERI mediated MAPK activation.
R-HSA-450321. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
R-HSA-5210891. Uptake and function of anthrax toxins.
R-HSA-5684264. MAP3K8 (TPL2)-dependent MAPK1/3 activation.
SignaLinkiP45985.
SIGNORiP45985.

Miscellaneous databases

ChiTaRSiMAP2K4. human.
EvolutionaryTraceiP45985.
GeneWikiiMAP2K4.
GenomeRNAii6416.
PMAP-CutDBP45985.
PROiP45985.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000065559.
CleanExiHS_MAP2K4.
ExpressionAtlasiP45985. baseline and differential.
GenevisibleiP45985. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMP2K4_HUMAN
AccessioniPrimary (citable) accession number: P45985
Secondary accession number(s): B2R7N7
, B3KYB2, D3DTS5, Q5U0B8, Q6FHX4, Q6P9H2, Q6PIE6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: November 2, 2016
This is version 173 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.