Q16659 (MK06_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase 6
Short name=MAP kinase 6
Short name=MAPK 6
EC=2.7.11.24

Alternative name(s):
Extracellular signal-regulated kinase 3
Short name=ERK-3
MAP kinase isoform p97
Short name=p97-MAPK

Gene names

Name:	MAPK6
Synonyms:	ERK3, PRKM6

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	721 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, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. 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-189.
Subunit structure	Heterodimer with ERK4/MAPK4. Interacts with (via FRIEDE motif) MAPKAPK5 By similarity. Interacts with UBE3A; this interaction may be indirect and mediated by HERC2, possibly via HERC2 interaction with NEURL4. Ref.10
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: Translocates to the cytoplasm following interaction with MAPKAPK5 By similarity.
Tissue specificity	Highest expression in the skeletal muscle, followed by the brain. Also found in heart, placenta, lung, liver, pancreas, kidney and skin fibroblasts.
Domain	In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases By similarity.
Post-translational modification	Phosphorylated at Ser-189 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites. Ref.9
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.

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	3D-structure 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 Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
vif	P12504	2	EBI-1384105,EBI-779991	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 721

721

Mitogen-activated protein kinase 6

PRO_0000186257

Regions

Domain

20 – 316

297

Protein kinase

Nucleotide binding

26 – 34

9

ATP By similarity

Motif

189 – 191

3

SEG motif

Motif

332 – 337

6

FRIEDE motif

Sites

Active site

152

1

Proton acceptor By similarity

Binding site

49

1

ATP By similarity

Amino acid modifications

Modified residue

189

1

Phosphoserine; by PAK1, PAK2 and PAK3 Ref.6 Ref.7 Ref.9

Natural variations

Natural variant

290

1

L → V. Ref.5 Ref.11
Corresponds to variant rs35697691 [ dbSNP | Ensembl ].

VAR_042256

Secondary structure

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721

Helix Strand Turn

Details...

Beta strand

14 – 16

3

Turn

17 – 19

3

Beta strand

20 – 25

6

Beta strand

34 – 39

6

Turn

40 – 42

3

Beta strand

45 – 52

8

Helix

56 – 70

15

Beta strand

80 – 84

5

Beta strand

102 – 109

8

Beta strand

112 – 114

3

Helix

115 – 119

5

Helix

126 – 145

20

Helix

155 – 157

3

Beta strand

158 – 161

4

Turn

162 – 165

4

Beta strand

166 – 169

4

Helix

190 – 192

3

Helix

200 – 204

5

Helix

211 – 227

17

Helix

237 – 247

11

Helix

253 – 260

8

Helix

265 – 270

6

Helix

278 – 281

4

Helix

287 – 294

8

Helix

301 – 303

3

Helix

307 – 311

5

Helix

314 – 317

4

Sequences

	Sequence		Length	Mass (Da)
	Q16659 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: DAA3AAA9B98BB31F	FASTA	721	82,681
	10 20 30 40 50 60 MAEKFESLMN IHGFDLGSRY MDLKPLGCGG NGLVFSAVDN DCDKRVAIKK IVLTDPQSVK 70 80 90 100 110 120 HALREIKIIR RLDHDNIVKV FEILGPSGSQ LTDDVGSLTE LNSVYIVQEY METDLANVLE 130 140 150 160 170 180 QGPLLEEHAR LFMYQLLRGL KYIHSANVLH RDLKPANLFI NTEDLVLKIG DFGLARIMDP 190 200 210 220 230 240 HYSHKGHLSE GLVTKWYRSP RLLLSPNNYT KAIDMWAAGC IFAEMLTGKT LFAGAHELEQ 250 260 270 280 290 300 MQLILESIPV VHEEDRQELL SVIPVYIRND MTEPHKPLTQ LLPGISREAL DFLEQILTFS 310 320 330 340 350 360 PMDRLTAEEA LSHPYMSIYS FPMDEPISSH PFHIEDEVDD ILLMDETHSH IYNWERYHDC 370 380 390 400 410 420 QFSEHDWPVH NNFDIDEVQL DPRALSDVTD EEEVQVDPRK YLDGDREKYL EDPAFDTNYS 430 440 450 460 470 480 TEPCWQYSDH HENKYCDLEC SHTCNYKTRS SSYLDNLVWR ESEVNHYYEP KLIIDLSNWK 490 500 510 520 530 540 EQSKEKSDKK GKSKCERNGL VKAQIALEEA SQQLAGKERE KNQGFDFDSF IAGTIQLSSQ 550 560 570 580 590 600 HEPTDVVDKL NDLNSSVSQL ELKSLISKSV SQEKQEKGMA NLAQLEALYQ SSWDSQFVSG 610 620 630 640 650 660 GEDCFFINQF CEVRKDEQVE KENTYTSYLD KFFSRKEDTE MLETEPVEDG KLGERGHEEG 670 680 690 700 710 720 FLNNSGEFLF NKQLESIGIP QFHSPVGSPL KSIQATLTPS AMKSSPQIPH QTYSSILKHL N

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of p97MAPK, a novel human homolog of rat ERK-3." Zhu A.X., Zhao Y., Moller D.E., Flier J.S. Mol. Cell. Biol. 14:8202-8211(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal skeletal muscle.
[2]	"Primary structure, expression and chromosomal locus of a human homolog of rat ERK3." Meloche S., Beatty B.G., Pellerin J. Oncogene 13:1575-1579(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Smooth muscle.
[3]	"ERK-3 cDNA clone isolated from human oral cancer." Saranath D., Mahale A., Rai R., Dedhia P. Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Oral cancer.
[4]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Esophageal carcinoma.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-290. Tissue: Placenta.
[6]	"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-189, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[7]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-189, MASS SPECTROMETRY.
[8]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[9]	"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-189.
[10]	"Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes." Martinez-Noel G., Galligan J.T., Sowa M.E., Arndt V., Overton T.M., Harper J.W., Howley P.M. Mol. Cell. Biol. 32:3095-3106(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBE3A AND NEURL4.
[11]	"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: VARIANT [LARGE SCALE ANALYSIS] VAL-290.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X80692 mRNA. Translation: CAA56709.1.
L77964 mRNA. Translation: AAA98769.1.
AF420474 mRNA. Translation: AAL17605.1.
CR749401 mRNA. Translation: CAH18246.1.
BC035492 mRNA. Translation: AAH35492.1.

IPI

IPI00003431.

PIR

A56352.

RefSeq

NP_002739.1. NM_002748.3.

UniGene

Hs.411847.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2I6L	X-ray	2.25	A/B	9-327	[»]

ProteinModelPortal

Q16659.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q16659. 19 interactions.

MINT

MINT-8247530.

STRING

9606.ENSP00000261845.

PTM databases

PhosphoSite

Q16659.

Polymorphism databases

DMDM

2499596.

Proteomic databases

PaxDb

Q16659.

PRIDE

Q16659.

Protocols and materials databases

DNASU

5597.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000261845; ENSP00000261845; ENSG00000069956.

GeneID

5597.

KEGG

hsa:5597.

UCSC

uc002abp.3. human.

Organism-specific databases

CTD

5597.

GeneCards

GC15P052311.

HGNC

HGNC:6879. MAPK6.

HPA

CAB005184.
HPA030262.

MIM

602904. gene.

neXtProt

NX_Q16659.

PharmGKB

PA30624.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233020.

HOVERGEN

HBG104376.

InParanoid

Q16659.

KO

K06855.

OMA

SLHPFHI.

OrthoDB

EOG45HRWS.

PhylomeDB

Q16659.

Enzyme and pathway databases

BRENDA

2.7.11.24. 2681.

SignaLink

Q16659.

Gene expression databases

Bgee

Q16659.

CleanEx

HS_MAPK6.

Genevestigator

Q16659.

GermOnline

ENSG00000069956. 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

Q16659.

ChEMBL

CHEMBL5121.

EvolutionaryTrace

Q16659.

GenomeRNAi

5597.

NextBio

21724.

SOURCE

Search...

Entry information

Entry name

MK06_HUMAN

Accession

Primary (citable) accession number: Q16659
Secondary accession number(s): Q68DH4, Q8IYN8

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	May 29, 2013
This is version 126 of the entry and version 1 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.