P31152 (MK04_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase 4
Short name=MAP kinase 4
Short name=MAPK 4
EC=2.7.11.24

Alternative name(s):
Extracellular signal-regulated kinase 4
Short name=ERK-4
MAP kinase isoform p63
Short name=p63-MAPK

Gene names

Name:	MAPK4
Synonyms:	ERK4, PRKM4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	587 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Activated by phosphorylation at Ser-186.
Subunit structure	Homodimer. Heterodimer with ERK3/MAPK6. Interacts with (via FRIEDE motif) MAPKAPK5 By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: Translocates to the cytoplasm following interaction with MAPKAPK5 By similarity.
Tissue specificity	High expression in heart and brain.
Domain	The FRIEDE motif is required for docking MAPKAPK5 By similarity. In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases.
Post-translational modification	Phosphorylated at Ser-186 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites. Ref.5
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.
Sequence caution	The sequence CAA42411.1 differs from that shown. Reason: Frameshift at several positions.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase activity Traceable author statement PubMed 7969157. Source: ProtInc protein homodimerization activity Inferred from sequence or structural similarity. Source: UniProtKB protein kinase binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HSP90AB1	P08238	2	EBI-3906061,EBI-352572

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 587	587	Mitogen-activated protein kinase 4		PRO_0000186254
Regions
	Domain	20 – 312	293	Protein kinase
	Nucleotide binding	26 – 34	9	ATP By similarity
	Motif	186 – 188	3	SEG motif
	Motif	328 – 333	6	FRIEDE motif
Sites
	Active site	149	1	Proton acceptor By similarity
	Binding site	49	1	ATP By similarity
Amino acid modifications
	Modified residue	186	1	Phosphoserine; by PAK1, PAK2 and PAK3 Ref.4 Ref.5
Natural variations
	Natural variant	38	1	V → M. Ref.6 Corresponds to variant rs3752087 [ dbSNP | Ensembl ].		VAR_042254
	Natural variant	371	1	R → P. Ref.6 Corresponds to variant rs3752089 [ dbSNP | Ensembl ].		VAR_042255

Sequences

	Sequence		Length	Mass (Da)
	P31152 [UniParc]. Last modified November 25, 2008. Version 2. Checksum: 71DB32D1E63EF8EE	FASTA	587	65,922
	10 20 30 40 50 60 MAEKGDCIAS VYGYDLGGRF VDFQPLGFGV NGLVLSAVDS RACRKVAVKK IALSDARSMK 70 80 90 100 110 120 HALREIKIIR RLDHDNIVKV YEVLGPKGTD LQGELFKFSV AYIVQEYMET DLARLLEQGT 130 140 150 160 170 180 LAEEHAKLFM YQLLRGLKYI HSANVLHRDL KPANIFISTE DLVLKIGDFG LARIVDQHYS 190 200 210 220 230 240 HKGYLSEGLV TKWYRSPRLL LSPNNYTKAI DMWAAGCILA EMLTGRMLFA GAHELEQMQL 250 260 270 280 290 300 ILETIPVIRE EDKDELLRVM PSFVSSTWEV KRPLRKLLPE VNSEAIDFLE KILTFNPMDR 310 320 330 340 350 360 LTAEMGLQHP YMSPYSCPED EPTSQHPFRI EDEIDDIVLM AANQSQLSNW DTCSSRYPVS 370 380 390 400 410 420 LSSDLEWRPD RCQDASEVQR DPRAGSAPLA EDVQVDPRKD SHSSSERFLE QSHSSMERAF 430 440 450 460 470 480 EADYGRSCDY KVGSPSYLDK LLWRDNKPHH YSEPKLILDL SHWKQAAGAP PTATGLADTG 490 500 510 520 530 540 AREDEPASLF LEIAQWVKST QGGPEHASPP ADDPERRLSA SPPGRPAPVD GGASPQFDLD 550 560 570 580 VFISRALKLC TKPEDLPDNK LGDLNGACIP EHPGDLVQTE AFSKERW

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Heterogeneous expression of four MAP kinase isoforms in human tissues." Gonzalez F.A., Raden D.L., Rigby M.R., Davis R.J. FEBS Lett. 304:170-178(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"DNA sequence and analysis of human chromosome 18." Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J. , Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S. Nature 437:551-555(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[5]	"Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway." Deleris P., Trost M., Topisirovic I., Tanguay P.L., Borden K.L., Thibault P., Meloche S. J. Biol. Chem. 286:6470-6478(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-186.
[6]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] MET-38 AND PRO-371.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases
EMBL GenBank DDBJ	X59727 mRNA. Translation: CAA42411.1. Frameshift. AK295058 mRNA. No translation available. AC012433 Genomic DNA. No translation available. AC090395 Genomic DNA. No translation available.
IPI	IPI00010156.
PIR	S23429.
RefSeq	NP_002738.2. NM_002747.3.
UniGene	Hs.433728.
3D structure databases
ProteinModelPortal	P31152.
ModBase	Search...
Protein-protein interaction databases
IntAct	P31152. 3 interactions.
STRING	9606.ENSP00000383234.
PTM databases
PhosphoSite	P31152.
Polymorphism databases
DMDM	215274102.
Proteomic databases
PaxDb	P31152.
PRIDE	P31152.
Protocols and materials databases
DNASU	5596.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000400384; ENSP00000383234; ENSG00000141639. ENST00000576626; ENSP00000459073; ENSG00000262673.
GeneID	5596.
KEGG	hsa:5596.
UCSC	uc002lev.3. human.
Organism-specific databases
CTD	5596.
GeneCards	GC18P048125.
H-InvDB	HIX0027373.
HGNC	HGNC:6878. MAPK4.
HPA	CAB025868. HPA007461.
MIM	176949. gene.
neXtProt	NX_P31152.
PharmGKB	PA30623.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233020.
HOVERGEN	HBG104376.
InParanoid	P31152.
KO	K06855.
OMA	RCQDASE.
OrthoDB	EOG4PG60R.
Enzyme and pathway databases
BRENDA	2.7.11.24. 2681.
Gene expression databases
ArrayExpress	P31152.
Bgee	P31152.
CleanEx	HS_MAPK4.
Genevestigator	P31152.
GermOnline	ENSG00000141639. Homo sapiens.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR008350. MAPK_ERK3/4. 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]
PRINTS	PR01771. ERK3ERK4MAPK.
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	P31152.
ChEMBL	CHEMBL5759.
GenomeRNAi	5596.
NextBio	21720.
SOURCE	Search...

Entry information

Entry name

MK04_HUMAN

Accession

Primary (citable) accession number: P31152

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	November 25, 2008
Last modified:	May 1, 2013
This is version 125 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.