Dual specificity mitogen-activated protein kinase kinase 4

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P47809 (MP2K4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 3, 2013. Version 109. History...

Clusters with 100%, 90%, 50% identity |

Documents (3) |

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Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
Dual specificity mitogen-activated protein kinase kinase 4
Short name=MAP kinase kinase 4
Short name=MAPKK 4
EC=2.7.12.2

Alternative name(s):
C-JUN N-terminal kinase kinase 1
Short name=JNK kinase 1
Short name=JNKK 1
JNK-activating kinase 1
MAPK/ERK kinase 4
Short name=MEK 4
SAPK/ERK kinase 1
Short name=SEK1

Gene names

Name:	Map2k4
Synonyms:	Jnkk1, Mek4, Mkk4, Prkmk4, Sek1, Serk1, Skk1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	397 AA.
Sequence status	Complete.
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. 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. Ref.1 Ref.3 Ref.4 Ref.6 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	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. Ref.4
Subunit structure	Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 By similarity. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3 By similarity. Ref.7 Ref.14
Subcellular location	Cytoplasm. Nucleus Ref.4.
Tissue specificity	Strong expression is detected in most of the central nervous system and in liver and thymus during early stages of development. While expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of expression in the central nervous system persists throughout postnatal development and remained at a stable level in adult brain. Ref.5
Domain	The DVD domain (residues 362-385) 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 By similarity. The D domain (residues 35-50) contains a conserved docking site and is required for the binding to MAPk substrates.
Post-translational modification	Activated by phosphorylation on Ser-255 and Thr-259 by MAP kinase kinase kinases (MAP3Ks) By similarity.
Disruption phenotype	Causes irregular alignment of Purkinje cells in the cerebellum and delayed radial migration in the cortex during brain development. The cardiac-specific deletion prevents pathological cardiac hypertrophy. Ref.9 Ref.10
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
Biological process	Apoptosis Stress response
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of JUN kinase activity Inferred from sequence orthology PubMed 17681137. Source: MGI apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cellular response to mechanical stimulus Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 397

397

Dual specificity mitogen-activated protein kinase kinase 4

PRO_0000086382

Regions

Domain

100 – 366

267

Protein kinase

Nucleotide binding

106 – 114

ATP By similarity

Region

35 – 50

D domain By similarity

Region

362 – 385

DVD domain By similarity

Compositional bias

5 – 17

Gly/Ser-rich

Sites

Active site

227

Proton acceptor By similarity

Binding site

129

ATP

Amino acid modifications

Modified residue

Phosphoserine By similarity

Modified residue

255

Phosphoserine; by MAP3K By similarity

Modified residue

259

Phosphothreonine; by MAP3K By similarity

Experimental info

Mutagenesis

129

K → R: Loss of ATP-binding. Ref.1

Sequences

Sequence

Length

Mass (Da)

Tools

P47809 [UniParc].

Last modified November 1, 1997. Version 2.
Checksum: B99C6688184E5B3D
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FASTA

397

44,114

        10         20         30         40         50         60 
MAAPSPSGGG GSGGGGGTPG PIGPPASGHP AVSSMQGKRK ALKLNFANPP VKSTARFTLN 

        70         80         90        100        110        120 
PNTTGVQNPH IERLRTHSIE SSGKLKISPE QHWDFTAEDL KDLGEIGRGA YGSVNKMVHK 

       130        140        150        160        170        180 
PSGQIMAVKR IRSTVDEKEQ KQLLMDLDVV MRSSDCPYIV QFYGALFREG DCWICMELMS 

       190        200        210        220        230        240 
TSFDKFYKYV YSVLDDVIPE EILGKITLAT VKALNHLKEN LKIIHRDIKP SNILLDRSGN 

       250        260        270        280        290        300 
IKLCDFGISG QLVDSIAKTR DAGCRPYMAP ERIDPSASRQ GYDVRSDVWS LGITLYELAT 

       310        320        330        340        350        360 
GRFPYPKWNS VFDQLTQVVK GDPPQLSNSE EREFSPSFIN FVNLCLTKDE SKRPKYKELL 

       370        380        390 
KHPFILMYEE RTVEVACYVC KILDQMPATP SSPMYVD

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References

[1]	"Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun." Sanchez I., Hughes R.T., Mayer B.J., Yee K., Woodgett J.R., Avruch J., Kyriakis J.M., Zon L.I. Nature 372:794-798(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MUTAGENESIS OF LYS-129. Tissue: Embryo.
[2]	Zon L.I. Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[3]	"SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development." Swat W., Fujikawa K., Ganiatsas S., Yang D., Xavier R.J., Harris N.L., Davidson L., Ferrini R., Davis R.J., Labow M.A., Flavell R.A., Zon L.I., Alt F.W. Immunity 8:625-634(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[4]	"The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases." Tournier C., Whitmarsh A.J., Cavanagh J., Barrett T., Davis R.J. Mol. Cell. Biol. 19:1569-1581(1999) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, SUBCELLULAR LOCATION, FUNCTION OF THE MKK/JNK PATHWAY.
[5]	"Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice." Lee J.K., Hwang W.S., Lee Y.D., Han P.L. Brain Res. Mol. Brain Res. 66:133-140(1999) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[6]	"MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines." Tournier C., Dong C., Turner T.K., Jones S.N., Flavell R.A., Davis R.J. Genes Dev. 15:1419-1426(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"A subdomain of MEKK1 that is critical for binding to MKK4." Tu Z., Mooney S.M., Lee F.S. Cell. Signal. 15:65-77(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, INTERACTION WITH MAP3K1/MEKK1.
[8]	"Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells." Kishimoto H., Nakagawa K., Watanabe T., Kitagawa D., Momose H., Seo J., Nishitai G., Shimizu N., Ohata S., Tanemura S., Asaka S., Goto T., Fukushi H., Yoshida H., Suzuki A., Sasaki T., Wada T., Penninger J.M., Nishina H., Katada T. J. Biol. Chem. 278:16595-16601(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death." Wang X., Nadarajah B., Robinson A.C., McColl B.W., Jin J.W., Dajas-Bailador F., Boot-Handford R.P., Tournier C. Mol. Cell. Biol. 27:7935-7946(2007) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[10]	"Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth." Liu W., Zi M., Jin J., Prehar S., Oceandy D., Kimura T.E., Lei M., Neyses L., Weston A.H., Cartwright E.J., Wang X. Circ. Res. 104:905-914(2009) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[11]	"Differential regulation and properties of MAPKs." Raman M., Chen W., Cobb M.H. Oncogene 26:3100-3112(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ENZYME REGULATION.
[12]	"Diverse physiological functions of MKK4 and MKK7 during early embryogenesis." Asaoka Y., Nishina H. J. Biochem. 148:393-401(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[13]	"The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7." Haeusgen W., Herdegen T., Waetzig V. Eur. J. Cell Biol. 90:536-544(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON REGULATION, REVIEW ON FUNCTION.
[14]	"JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors." Lee C.M., Onesime D., Reddy C.D., Dhanasekaran N., Reddy E.P. Proc. Natl. Acad. Sci. U.S.A. 99:14189-14194(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SPAG9.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U18310 mRNA. Translation: AAB81554.1.
IPI	IPI00112335.
PIR	S52423.
RefSeq	NP_033183.1. NM_009157.4.
UniGene	Mm.412922.
3D structure databases
ProteinModelPortal	P47809.
SMR	P47809. Positions 93-386.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-869N.
IntAct	P47809. 1 interaction.
STRING	10090.ENSMUSP00000041282.
PTM databases
PhosphoSite	P47809.
Proteomic databases
PaxDb	P47809.
PRIDE	P47809.
Protocols and materials databases
DNASU	26398.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000046963; ENSMUSP00000041282; ENSMUSG00000033352.
GeneID	26398.
KEGG	mmu:26398.
Organism-specific databases
CTD	6416.
MGI	MGI:1346869. Map2k4.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000234206.
HOVERGEN	HBG108518.
InParanoid	P47809.
KO	K04430.
OMA	GITLMEV.
Enzyme and pathway databases
BRENDA	2.7.12.2. 3474.
Reactome	REACT_107772. Immune System.
Gene expression databases
ArrayExpress	P47809.
Bgee	P47809.
CleanEx	MM_MAP2K4.
Genevestigator	P47809.
GermOnline	ENSMUSG00000033352. Mus musculus.
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	P47809.
ChEMBL	CHEMBL2201.
NextBio	304351.
SOURCE	Search...

Entry information

Entry name

MP2K4_MOUSE

Accession

Primary (citable) accession number: P47809

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	November 1, 1997
Last modified:	April 3, 2013
This is version 109 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents