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 ChEMBL: 4948 GeneCards: MAP2K5 Gene

EC number

2.7.12.2

Gene ontology
Molecular function	• protein kinase activity • protein serine/threonine kinase activity • MAP kinase kinase activity • protein tyrosine kinase activity • protein binding • ATP binding • metal ion binding
Cellular component	• intracellular • 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:
67.54 – 67.81 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]

Function

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 2 Zhou G, Bao ZQ, Dixon JE (May 1995). "Components of a new human protein kinase signal transduction pathway". The Journal of Biological Chemistry 270 (21): 12665–9. doi:10.1074/jbc.270.21.12665. PMID 7759517.
1 2 "Entrez Gene: MAP2K5 mitogen-activated protein kinase kinase 5".
1 2 Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
↑ Diaz-Meco MT, Moscat J (Feb 2001). "MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling". Molecular and Cellular Biology 21 (4): 1218–27. doi:10.1128/MCB.21.4.1218-1227.2001. PMC 99575. PMID 11158308.
↑ Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.

English JM, Vanderbilt CA, Xu S, Marcus S, Cobb MH (Dec 1995). "Isolation of MEK5 and differential expression of alternatively spliced forms". The Journal of Biological Chemistry 270 (48): 28897–902. doi:10.1074/jbc.270.48.28897. PMID 7499418.
Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD (Dec 1997). "BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C". The EMBO Journal 16 (23): 7054–66. doi:10.1093/emboj/16.23.7054. PMC 1170308. PMID 9384584.
Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD (Oct 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, Shivakumar L, White MA, Cobb MH (Oct 1999). "Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control". The Journal of Biological Chemistry 274 (44): 31588–92. doi:10.1074/jbc.274.44.31588. PMID 10531364.
Chao TH, Hayashi M, Tapping RI, Kato Y, Lee JD (Dec 1999). "MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway". The Journal of Biological Chemistry 274 (51): 36035–8. doi:10.1074/jbc.274.51.36035. PMID 10593883.
Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
Diaz-Meco MT, Moscat J (Feb 2001). "MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling". Molecular and Cellular Biology 21 (4): 1218–27. doi:10.1128/MCB.21.4.1218-1227.2001. PMC 99575. PMID 11158308.
Nicol RL, Frey N, Pearson G, Cobb M, Richardson J, Olson EN (Jun 2001). "Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy". The EMBO Journal 20 (11): 2757–67. doi:10.1093/emboj/20.11.2757. PMC 125475. PMID 11387209.
Dinev D, Jordan BW, Neufeld B, Lee JD, Lindemann D, Rapp UR, Ludwig S (Sep 2001). "Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells". EMBO Reports 2 (9): 829–34. doi:10.1093/embo-reports/kve177. PMC 1084032. PMID 11520859.
Weldon CB, Scandurro AB, Rolfe KW, Clayton JL, Elliott S, Butler NN, Melnik LI, Alam J, McLachlan JA, Jaffe BM, Beckman BS, Burow ME (Aug 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.
Mehta PB, Jenkins BL, McCarthy L, Thilak L, Robson CN, Neal DE, Leung HY (Mar 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, Peggie M, Cohen P (Jun 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". The Biochemical Journal 372 (Pt 2): 567–75. doi:10.1042/BJ20030193. PMC 1223423. PMID 12628002.
Huang J, Tu Z, Lee FS (Apr 2003). "Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity". Biochemical and Biophysical Research Communications 303 (2): 532–40. doi:10.1016/S0006-291X(03)00387-5. PMID 12659851.
Lamark T, Perander M, Outzen H, Kristiansen K, Øvervatn A, Michaelsen E, Bjørkøy G, Johansen T (Sep 2003). "Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins". The Journal of Biological Chemistry 278 (36): 34568–81. doi:10.1074/jbc.M303221200. PMID 12813044.
Cameron SJ, Abe J, Malik S, Che W, Yang J (Jan 2004). "Differential role of MEK5alpha and MEK5beta in BMK1/ERK5 activation". The Journal of Biological Chemistry 279 (2): 1506–12. doi:10.1074/jbc.M308755200. PMID 14583600.
Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.
Raviv Z, Kalie E, Seger R (Apr 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". Journal of Cell Science 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 CDK12 CDC2L5 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

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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