MAP2K5

Mitogen-activated protein kinase kinase 5

PDB rendering based on 1wi0.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
2NPT, 2O2V, 4IC7

Identifiers

Symbols

MAP2K5 ; HsT17454; MAPKK5; MEK5; PRKMK5

External IDs

OMIM: 602520 MGI: 1346345 HomoloGene: 115933 IUPHAR: 2066 ChEMBL: 4948 GeneCards: MAP2K5 Gene

EC number

2.7.12.2

Gene ontology
Molecular function	• protein kinase activity • protein serine/threonine kinase activity • protein tyrosine kinase activity • protein binding • ATP binding • metal ion binding
Cellular component	• nucleus • spindle • cytosol
Biological process	• negative regulation of transcription from RNA polymerase II promoter • activation of MAPK activity • signal transduction • heart development • peptidyl-tyrosine phosphorylation • positive regulation of cell growth • negative regulation of NF-kappaB transcription factor activity • negative regulation of heterotypic cell-cell adhesion • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation of interleukin-8 biosynthetic process • positive regulation of transcription from RNA polymerase II promoter • neurotrophin TRK receptor signaling pathway • positive regulation of epithelial cell proliferation • positive regulation of protein metabolic process • negative regulation of response to cytokine stimulus • ERK5 cascade • cellular response to growth factor stimulus • cellular response to laminar fluid shear stress • negative regulation of cell migration involved in sprouting angiogenesis • negative regulation of chemokine (C-X-C motif) ligand 2 production • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 15:
67.84 – 68.1 Mb

Chr 9:
63.16 – 63.38 Mb

PubMed search

Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the MAP2K5 gene.^[1]^[2]

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been described.^[2]

Upstream

This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs).

Downstream

This kinase specifically interacts with and activates MAPK7/ERK5.

Interactions

MAP2K5 has been shown to interact with MAPK7,^[1] MAP3K2,^[3] Protein kinase Mζ^[4] and MAP3K3.^[3]^[5]

References

↑ 1.0 1.1 Zhou G, Bao ZQ, Dixon JE (Jun 1995). "Components of a new human protein kinase signal transduction pathway". J Biol Chem 270 (21): 12665–9. doi:10.1074/jbc.270.21.12665. PMID 7759517.
↑ 2.0 2.1 "Entrez Gene: MAP2K5 mitogen-activated protein kinase kinase 5".
↑ 3.0 3.1 Sun, W; Kesavan K; Schaefer B C; Garrington T P; Ware M; Johnson N L; Gelfand E W; Johnson G L (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". J. Biol. Chem. (United States) 276 (7): 5093–100. doi:10.1074/jbc.M003719200. ISSN 0021-9258. PMID 11073940.
↑ Diaz-Meco, M T; Moscat J (Feb 2001). "MEK5, a New Target of the Atypical Protein Kinase C Isoforms in Mitogenic Signaling". Mol. Cell. Biol. (United States) 21 (4): 1218–27. doi:10.1128/MCB.21.4.1218-1227.2001. ISSN 0270-7306. PMC 99575. PMID 11158308.
↑ Bouwmeester, Tewis; Bauch Angela, Ruffner Heinz, Angrand Pierre-Olivier, Bergamini Giovanna, Croughton Karen, Cruciat Cristina, Eberhard Dirk, Gagneur Julien, Ghidelli Sonja, Hopf Carsten, Huhse Bettina, Mangano Raffaella, Michon Anne-Marie, Schirle Markus, Schlegl Judith, Schwab Markus, Stein Martin A, Bauer Andreas, Casari Georg, Drewes Gerard, Gavin Anne-Claude, Jackson David B, Joberty Gerard, Neubauer Gitte, Rick Jens, Kuster Bernhard, Superti-Furga Giulio (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. (England) 6 (2): 97–105. doi:10.1038/ncb1086. ISSN 1465-7392. PMID 14743216.

English JM, Vanderbilt CA, Xu S et al. (1996). "Isolation of MEK5 and differential expression of alternatively spliced forms". J. Biol. Chem. 270 (48): 28897–902. doi:10.1074/jbc.270.48.28897. PMID 7499418.
Kato Y, Kravchenko VV, Tapping RI et al. (1998). "BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C". EMBO J. 16 (23): 7054–66. doi:10.1093/emboj/16.23.7054. PMC 1170308. PMID 9384584.
Kato Y, Tapping RI, Huang S et al. (1998). "Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor". Nature 395 (6703): 713–6. doi:10.1038/27234. PMID 9790194.
English JM, Pearson G, Hockenberry T et al. (1999). "Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control". J. Biol. Chem. 274 (44): 31588–92. doi:10.1074/jbc.274.44.31588. PMID 10531364.
Chao TH, Hayashi M, Tapping RI et al. (2000). "MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway". J. Biol. Chem. 274 (51): 36035–8. doi:10.1074/jbc.274.51.36035. PMID 10593883.
Sun W, Kesavan K, Schaefer BC et al. (2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". J. Biol. Chem. 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
Diaz-Meco MT, Moscat J (2001). "MEK5, a New Target of the Atypical Protein Kinase C Isoforms in Mitogenic Signaling". Mol. Cell. Biol. 21 (4): 1218–27. doi:10.1128/MCB.21.4.1218-1227.2001. PMC 99575. PMID 11158308.
Nicol RL, Frey N, Pearson G et al. (2001). "Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy". EMBO J. 20 (11): 2757–67. doi:10.1093/emboj/20.11.2757. PMC 125475. PMID 11387209.
Dinev D, Jordan BW, Neufeld B et al. (2001). "Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells". EMBO Rep. 2 (9): 829–34. doi:10.1093/embo-reports/kve177. PMC 1084032. PMID 11520859.
Weldon CB, Scandurro AB, Rolfe KW et al. (2002). "Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray". Surgery 132 (2): 293–301. doi:10.1067/msy.2002.125389. PMID 12219026.
Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Mehta PB, Jenkins BL, McCarthy L et al. (2003). "MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion". Oncogene 22 (9): 1381–9. doi:10.1038/sj.onc.1206154. PMID 12618764.
Mody N, Campbell DG, Morrice N et al. (2003). "An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro". Biochem. J. 372 (Pt 2): 567–75. doi:10.1042/BJ20030193. PMC 1223423. PMID 12628002.
Huang J, Tu Z, Lee FS (2003). "Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity". Biochem. Biophys. Res. Commun. 303 (2): 532–40. doi:10.1016/S0006-291X(03)00387-5. PMID 12659851.
Lamark T, Perander M, Outzen H et al. (2003). "Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins". J. Biol. Chem. 278 (36): 34568–81. doi:10.1074/jbc.M303221200. PMID 12813044.
Cameron SJ, Abe J, Malik S et al. (2004). "Differential role of MEK5alpha and MEK5beta in BMK1/ERK5 activation". J. Biol. Chem. 279 (2): 1506–12. doi:10.1074/jbc.M308755200. PMID 14583600.
Ota T, Suzuki Y, Nishikawa T et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Bouwmeester T, Bauch A, Ruffner H et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.
Raviv Z, Kalie E, Seger R (2004). "MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation". J. Cell. Sci. 117 (Pt 9): 1773–84. doi:10.1242/jcs.01040. PMID 15075238.

PDB gallery

1wi0: Solution structure of the PB1 domain of mouse mitogen activated protein kinase kinase 5 (MAP2K5)

2npt: 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 2 phox domain (MAP3K2-phox)

2o2v: 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)

Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)

Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)

Non-specific serine/threonine protein kinases (EC 2.7.11.1)	LATS1 LATS2 MAST1 MAST2 STK38 STK38L CIT ROCK1 SGK SGK2 SGK3 Protein kinase B AKT1 AKT2 AKT3 Ataxia telangiectasia mutated Mammalian target of rapamycin EIF-2 kinases PKR HRI EIF2AK3 EIF2AK4 Wee1 WEE1

Pyruvate dehydrogenase kinase (EC 2.7.11.2)	PDK1 PDK2 PDK3

Dephospho-(reductase kinase) kinase (EC 2.7.11.3)	AMP-activated protein kinase α PRKAA1 PRKAA2 β PRKAB1 PRKAB2 γ PRKAG1 PRKAG2 PRKAG3

(3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)) (EC 2.7.11.4)	BCKDK BCKDHA BCKDHB

(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)	IDH2 IDH3A IDH3B IDH3G

(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)	STK4

Myosin-heavy-chain kinase (EC 2.7.11.7)	Aurora kinase Aurora A kinase Aurora B kinase

Fas-activated serine/threonine kinase (EC 2.7.11.8)	FASTK STK10

Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)	-

IκB kinase (EC 2.7.11.10)	CHUK IKK2 TBK1 IKBKE IKBKG IKBKAP

cAMP-dependent protein kinase (EC 2.7.11.11)	Protein kinase A PRKACG PRKACB PRKACA PRKY

cGMP-dependent protein kinase (EC 2.7.11.12)	Protein kinase G PRKG1

Protein kinase C (EC 2.7.11.13)	Protein kinase C Protein kinase Cζ PKC alpha PRKCB1 PRKCD PRKCE PRKCH PRKCG PRKCI PRKCQ Protein kinase N1 PKN2 PKN3

Rhodopsin kinase (EC 2.7.11.14)	Rhodopsin kinase

Beta adrenergic receptor kinase (EC 2.7.11.15)	Beta adrenergic receptor kinase Beta adrenergic receptor kinase-2

G-protein coupled receptor kinases (EC 2.7.11.16)	GRK4 GRK5 GRK6

Ca2+/calmodulin-dependent (EC 2.7.11.17)	BRSK2 CAMK1 CAMK2A CAMK2B CAMK2D CAMK2G CAMK4 MLCK CASK CHEK1 CHEK2 DAPK1 DAPK2 DAPK3 STK11 MAPKAPK2 MAPKAPK3 MAPKAPK5 MARK1 MARK2 MARK3 MARK4 MELK MKNK1 MKNK2 NUAK1 NUAK2 OBSCN PASK PHKG1 PHKG2 PIM1 PIM2 PKD1 PRKD2 PRKD3 PSKH1 SNF1LK2 KIAA0999 STK40 SNF1LK SNRK SPEG TSSK2 Kalirin TRIB1 TRIB2 TRIB3 TRIO Titin DCLK1

Myosin light-chain kinase (EC 2.7.11.18)	MYLK MYLK2 MYLK3 MYLK4

Phosphorylase kinase (EC 2.7.11.19)	PHKA1 PHKA2 PHKB PHKG1 PHKG2

Elongation factor 2 kinase (EC 2.7.11.20)	EEF2K STK19

Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)

Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4

Cyclin-dependent kinase (EC 2.7.11.22)	CDK1 CDK2 CDKL2 CDK3 CDK4 CDK5 CDKL5 CDK6 CDK7 CDK8 CDK9 CDK10 CDC2L5 CRKRS PCTK1 PCTK2 PCTK3 PFTK1 CDC2L1

(RNA-polymerase)-subunit kinase (EC 2.7.11.23)	RPS6KA5 RPS6KA4 P70S6 kinase P70-S6 Kinase 1 RPS6KB2 RPS6KA2 RPS6KA3 RPS6KA1 RPS6KC1

Mitogen-activated protein kinase (EC 2.7.11.24)	Extracellular signal-regulated MAPK1 MAPK3 MAPK4 MAPK6 MAPK7 MAPK12 MAPK15 C-Jun N-terminal MAPK8 MAPK9 MAPK10 P38 mitogen-activated protein MAPK11 MAPK13 MAPK14

MAP3K (EC 2.7.11.25)	MAP kinase kinase kinases MAP3K1 MAP3K2 MAP3K3 MAP3K4 MAP3K5 MAP3K6 MAP3K7 MAP3K8 RAFs ARAF BRAF KSR1 KSR2 MLKs MAP3K12 MAP3K13 MAP3K9 MAP3K10 MAP3K11 MAP3K7 ZAK CDC7 MAP3K14

Tau-protein kinase (EC 2.7.11.26)	TPK1 TTK GSK-3

(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)	-

Tropomyosin kinase (EC 2.7.11.28)	-

Low-density-lipoprotein receptor kinase (EC 2.7.11.29)	-

Receptor protein serine/threonine kinase (EC 2.7.11.30)	Bone morphogenetic protein receptors BMPR1 BMPR1A BMPR1B BMPR2 ACVR1 ACVR1B ACVR1C ACVR2A ACVR2B ACVRL1 Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)

MAP2K	MAP2K1 MAP2K2 MAP2K3 MAP2K4 MAP2K5 MAP2K6 MAP2K7

Biochemistry overview
Enzymes overview
By EC number: 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
2.1
- 2
- 3
- 4
- 5
- 6
- 7
  - 2.7.10
  - 11-12
- 8
3.1
- - 3.1.3.48
- 2
- 3
- 4
  - 3.4.21
  - 22
  - 23
  - 24
- 5
- 6
- 7
4.1
- 2
- 3
- 4
- 5
- 6
5.1
- 2
- 3
- 4
- 99
6.1-3
- 4
- 5-6

MAP2K5

Upstream

Downstream

Interactions

References

Further reading