Reviewed, UniProtKB/Swiss-Prot Q13163 (MP2K5_HUMAN)

Names and origin

Protein names

Recommended name:
    Dual specificity mitogen-activated protein kinase kinase 5
      Short name=MAP kinase kinase 5
      Short name=MAPKK 5
    EC=2.7.12.2
Alternative name(s):
    MAPK/ERK kinase 5
      Short name=MEK 5

Gene names

Name:	MAP2K5
Synonyms:	MEK5, MKK5, PRKMK5

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	448 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appear to play a critical role in protecting cells from stress-induced apopotosis, neuronal survival and cardiac development and angiogenesis. Ref.1 Ref.2
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Subunit structure	Interacts with PARD6A, MAP3K3 and MAPK7. Forms a complex with SQSTM1 and PRKCZ or PRKCI By similarity. Interacts with Yersinia yopJ. Ref.1 Ref.7
Tissue specificity	Expressed in many adult tissues. Abundant in heart and skeletal muscle.
Domain	Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of the OPR domain. This domain also mediates interactions with SQSTM1 and PARD6A By similarity.
Post-translational modification	Activated by phosphorylation on Ser/Thr by MAP kinase kinase kinases By similarity. Yersinia yopJ may acetylate Ser/Thr residues, preventing phosphorylation and activation, thus blocking the MAPK signaling pathway.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. Contains 1 OPR domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.1 Inferred from physical interaction. Source: IntAct 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...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GRB2	P62993	1	EBI-307294,EBI-401755
MAPK7	Q13164	1	EBI-307294,EBI-1213983

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform B (identifier: Q13163-1)

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.

Isoform A (identifier: Q13163-2)

The sequence of this isoform differs from the canonical sequence as follows:
     349-358: Missing.

Isoform C (identifier: Q13163-3)

The sequence of this isoform differs from the canonical sequence as follows:
     349-358: Missing.
     444-448: QQGPP → LASLPSPSPSV

Note: Incomplete sequence.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 448

448

Dual specificity mitogen-activated protein kinase kinase 5

PRO_0000086383

Regions

Domain

18 – 97

80

OPR

Domain

166 – 409

244

Protein kinase

Nucleotide binding

172 – 180

9

ATP By similarity

Region

18 – 25

8

Interaction with MAPK7 By similarity

Region

64 – 68

5

Interaction with MAP3K2/MAP3K3 By similarity

Region

117 – 131

15

Interaction with MAPK7 By similarity

Sites

Active site

283

1

Proton acceptor By similarity

Binding site

195

1

ATP

Amino acid modifications

Modified residue

133

1

Phosphoserine Ref.8

Modified residue

137

1

Phosphoserine

Modified residue

148

1

Phosphoserine

Modified residue

149

1

Phosphoserine

Modified residue

311

1

Phosphoserine Ref.1

Modified residue

315

1

Phosphothreonine Ref.1

Modified residue

316

1

Phosphotyrosine

Natural variations

Alternative sequence

349 – 358

10

Missing in isoform A and isoform C.

VSP_021825

Alternative sequence

444 – 448

5

QQGPP → LASLPSPSPSV in isoform C.

VSP_021826

Natural variant

118

1

H → R: dbSNP rs56241934. Ref.12

VAR_040823

Natural variant

427

1

A → V

VAR_040824

Natural variant

428

1

A → T: dbSNP rs55811347. Ref.12

VAR_046070

Experimental info

Mutagenesis

195

1

K → M: Inactivation. Ref.1

Mutagenesis

311

1

S → A: Inactivation. Ref.1

Mutagenesis

315

1

T → A: Inactivation. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

448

Helix Strand Turn

Details...

Beta strand

17 – 23

7

Turn

24 – 26

3

Beta strand

27 – 33

7

Helix

41 – 51

11

Beta strand

58 – 63

6

Beta strand

69 – 72

4

Helix

75 – 93

19

Turn

94 – 96

3

Beta strand

102 – 107

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform B [UniParc]. Last modified November 28, 2006. Version 2. Checksum: F23BB327E2A9C7DC	FASTA	448	50,112
	10 20 30 40 50 60 MLWLALGPFP AMENQVLVIR IKIPNSGAVD WTVHSGPQLL FRDVLDVIGQ VLPEATTTAF 70 80 90 100 110 120 EYEDEDGDRI TVRSDEEMKA MLSYYYSTVM EQQVNGQLIE PLQIFPRACK PPGERNIHGL 130 140 150 160 170 180 KVNTRAGPSQ HSSPAVSDSL PSNSLKKSSA ELKKILANGQ MNEQDIRYRD TLGHGNGGTV 190 200 210 220 230 240 YKAYHVPSGK ILAVKVILLD ITLELQKQIM SELEILYKCD SSYIIGFYGA FFVENRISIC 250 260 270 280 290 300 TEFMDGGSLD VYRKMPEHVL GRIAVAVVKG LTYLWSLKIL HRDVKPSNML VNTRGQVKLC 310 320 330 340 350 360 DFGVSTQLVN SIAKTYVGTN AYMAPERISG EQYGIHSDVW SLGISFMELA LGRFPYPQIQ 370 380 390 400 410 420 KNQGSLMPLQ LLQCIVDEDS PVLPVGEFSE PFVHFITQCM RKQPKERPAP EELMGHPFIV 430 440 QFNDGNAAVV SMWVCRALEE RRSQQGPP
	Isoform A. Checksum: 21246312F1640EE2	FASTA	438	48,968
	10 20 30 40 50 60 MLWLALGPFP AMENQVLVIR IKIPNSGAVD WTVHSGPQLL FRDVLDVIGQ VLPEATTTAF 70 80 90 100 110 120 EYEDEDGDRI TVRSDEEMKA MLSYYYSTVM EQQVNGQLIE PLQIFPRACK PPGERNIHGL 130 140 150 160 170 180 KVNTRAGPSQ HSSPAVSDSL PSNSLKKSSA ELKKILANGQ MNEQDIRYRD TLGHGNGGTV 190 200 210 220 230 240 YKAYHVPSGK ILAVKVILLD ITLELQKQIM SELEILYKCD SSYIIGFYGA FFVENRISIC 250 260 270 280 290 300 TEFMDGGSLD VYRKMPEHVL GRIAVAVVKG LTYLWSLKIL HRDVKPSNML VNTRGQVKLC 310 320 330 340 350 360 DFGVSTQLVN SIAKTYVGTN AYMAPERISG EQYGIHSDVW SLGISFMEIQ KNQGSLMPLQ 370 380 390 400 410 420 LLQCIVDEDS PVLPVGEFSE PFVHFITQCM RKQPKERPAP EELMGHPFIV QFNDGNAAVV 430 SMWVCRALEE RRSQQGPP
	Isoform C. Checksum: 574D15B06FD49134	FASTA	444	49,497
	10 20 30 40 50 60 MLWLALGPFP AMENQVLVIR IKIPNSGAVD WTVHSGPQLL FRDVLDVIGQ VLPEATTTAF 70 80 90 100 110 120 EYEDEDGDRI TVRSDEEMKA MLSYYYSTVM EQQVNGQLIE PLQIFPRACK PPGERNIHGL 130 140 150 160 170 180 KVNTRAGPSQ HSSPAVSDSL PSNSLKKSSA ELKKILANGQ MNEQDIRYRD TLGHGNGGTV 190 200 210 220 230 240 YKAYHVPSGK ILAVKVILLD ITLELQKQIM SELEILYKCD SSYIIGFYGA FFVENRISIC 250 260 270 280 290 300 TEFMDGGSLD VYRKMPEHVL GRIAVAVVKG LTYLWSLKIL HRDVKPSNML VNTRGQVKLC 310 320 330 340 350 360 DFGVSTQLVN SIAKTYVGTN AYMAPERISG EQYGIHSDVW SLGISFMEIQ KNQGSLMPLQ 370 380 390 400 410 420 LLQCIVDEDS PVLPVGEFSE PFVHFITQCM RKQPKERPAP EELMGHPFIV QFNDGNAAVV 430 440 SMWVCRALEE RRSLASLPSP SPSV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Components of a new human protein kinase signal transduction pathway." Zhou G., Bao Z.Q., Dixon J.E. J. Biol. Chem. 270:12665-12669(1995) [PubMed: 7759517] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), FUNCTION, INTERACTION WITH ERK5 AND MAPK7, MUTAGENESIS OF LYS-195; SER-311 AND THR-315, PHOSPHORYLATION AT SER-311 AND THR-315. Tissue: Fetal brain.
[2]	"BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C." Kato Y., Kravchenko V.V., Tapping R.I., Han J., Ulevitch R.J., Lee J.-D. EMBO J. 16:7054-7066(1997) [PubMed: 9384584] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS B AND C), FUNCTION. Tissue: Placenta.
[3]	Lee J.D. Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO C-TERMINUS OF ISOFORM C.
[4]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
[5]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B). Tissue: Brain.
[7]	"Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation." Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., Orth K. Science 312:1211-1214(2006) [PubMed: 16728640] [Abstract] Cited for: INTERACTION WITH YOPJ, ACETYLATION.
[8]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-133, MASS SPECTROMETRY.
[9]	"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: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-137; SER-148; SER-149; SER-311; THR-315 AND TYR-316, MASS SPECTROMETRY.
[10]	"Crystal structure of the complex of human mitogen activated protein kinase kinase 5 phox domain (MAP2K5-Phox) with human mitogen activated protein kinase kinase kinase 3 (MAP3K2B-Phox)." Structural genomics consortium (SGC) Submitted (NOV-2006) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 4-108 IN COMPLEX WITH MAP3K2.
[11]	"Crystal structure of the complex of human mitogen activated protein kinase kinase 5 phox domain (MAP2K5-Phox) with human mitogen activated protein kinase kinase kinase 3 (MAP3K3B-Phox)." Structural genomics consortium (SGC) Submitted (NOV-2006) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 4-108 IN COMPLEX WITH MAP3K3.
[12]	"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: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ARG-118; VAL-427 AND THR-428.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U25265 mRNA. Translation: AAA96146.1.
U71087 mRNA. Translation: AAB16851.1.
U71088 mRNA. Translation: AAB16852.2.
BT006780 mRNA. Translation: AAP35426.1.
CR542229 mRNA. Translation: CAG47025.1.
BC008838 mRNA. Translation: AAH08838.1.

IPI

IPI00158248.
IPI00185860.
IPI00219607.

RefSeq

NP_002748.1.
NP_660143.1.

UniGene

Hs.114198

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NPT	X-ray	1.75	A/C	5-108	[»]
2O2V	X-ray	1.83	A	5-108	[»]

SMR

Q13163. Positions 159-439.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-27558N.

IntAct

Q13163. 5 interactions.

STRING

Q13163.

PTM databases

PhosphoSite

Q13163.

Proteomic databases

PRIDE

Q13163.

Genome annotation databases

Ensembl

ENST00000178640; ENSP00000178640; ENSG00000137764; Homo sapiens. [Genome view]

GeneID

5607.

KEGG

hsa:5607.

UCSC

uc002aqu.1. human.
uc002aqv.1. human.

Organism-specific databases

CTD

5607.

GeneCards

GC15P065622.

HGNC

HGNC:6845. MAP2K5.

HPA

CAB022094.

MIM

602520. gene.

PharmGKB

PA30590.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04411.

HOGENOM

HBG755340.

HOVERGEN

Q13163.

InParanoid

Q13163.

OMA

HAMENQV.

OrthoDB

EOG9TB6WM.

PhylomeDB

Q13163.

Enzyme and pathway databases

BRENDA

2.7.12.2. 247.

Pathway_Interaction_DB

mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_11061. Signalling by NGF.

Gene expression databases

ArrayExpress

Q13163.

Bgee

Q13163.

CleanEx

HS_MAP2K5.

Genevestigator

Q13163.

GermOnline

ENSG00000137764. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000270. OPR_PB1.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_prot_kinase-like_dom.
IPR008271. Ser/Thr_prot_kinase_AS.
IPR002290. Ser/Thr_prot_kinase_dom.
[Graphical view]

Pfam

PF00564. PB1. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00666. PB1. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

21792.

SOURCE

Search...

Entry information

Entry name

MP2K5_HUMAN

Accession

Primary (citable) accession number: Q13163
Secondary accession number(s): Q92961, Q92962

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 28, 2006
Last modified:	February 9, 2010
This is version 103 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.