Dual specificity mitogen-activated protein kinase kinase 5

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

Gene names

Name:	MAP2K5
Synonyms:	MEK5, MKK5, PRKMK5

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	448 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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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.
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.
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.

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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
Gene Ontology (GO)
Biological process	protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro signal transduction Ref.1 Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro 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: InterPro protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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Binary interactions

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

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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
Notes: Incomplete sequence.

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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

311

1

Phosphoserine

Modified residue

315

1

Phosphothreonine

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.

VAR_040823

Natural variant

427

1

A → V

VAR_040824

Natural variant

428

1

A → T: dbSNP rs55811347.

VAR_046070

Experimental info

Mutagenesis

195

1

K → M: Inactivation

Mutagenesis

311

1

S → A: Inactivation

Mutagenesis

315

1

T → A: Inactivation

Secondary structure

1

.

448

Helix Strand Turn

Details...

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Sequences

Sequence		Length	Mass (Da)
Isoform B [UniParc]. Last modified November 28, 2006. Version 2. Checksum: F23BB327E2A9C7DC Show »	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 « Hide
Isoform A [UniParc]. Checksum: 21246312F1640EE2 Show »		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 « Hide
Isoform C [UniParc]. Checksum: 574D15B06FD49134 Show »		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 « Hide

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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]	"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.
[9]	"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.
[10]	"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. 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.

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Cross-references

Sequence databases

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.

RefSeq

NP_002748.1.
NP_660143.1.

UniGene

Hs.114198
Hs.646519

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NPT	X-ray	1.75	A/C	4-108	[»]
2O2V	X-ray	1.83	A	4-108	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:27558N.

IntAct

Q13163.

PTM databases

PhosphoSite

Q13163.

Genome annotation databases

Ensembl

ENSG00000137764. Homo sapiens. [Contig view]

GeneID

5607.

KEGG

hsa:5607.

Organism-specific databases

HGNC

HGNC:6845. MAP2K5.

MIM

602520. gene.

PharmGKB

PA30590.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

Q13163.

HOVERGEN

Q13163.

Gene expression databases

ArrayExpress

Q13163.

CleanEx

HS_MAP2K5.

GermOnline

ENSG00000137764. Homo sapiens.

Family and domain databases

InterPro

IPR000270. OPR_PB1.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_bd_CS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[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...

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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:	November 25, 2008
This is version 87 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents