MAPK7

MAPK7
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2Q8Y, 4B99, 4IC7, 4IC8, 4ZSJ, 4ZSL, 5BYZ, 5BYY, 4ZSG
Identifiers
Aliases	MAPK7, BMK1, ERK4, ERK5, PRKM7, mitogen-activated protein kinase 7
External IDs	OMIM: 602521; MGI: 1346347; HomoloGene: 2060; GeneCards: MAPK7; OMA:MAPK7 - orthologs
Gene location (Human)
Chr.	Chromosome 17 (human)
End	19,383,544 bp
Gene location (Mouse)
Chr.	Chromosome 11 (mouse)
End	61,494,406 bp
RNA expression pattern
	Top expressed in
	ganglionic eminence; ; stromal cell of endometrium; ; popliteal artery; ; tibial arteries; ; sural nerve; ; ventricular zone; ; ectocervix; ; granulocyte; ; right ovary; ; skin of leg;
	Top expressed in
	granulocyte; ; tail of embryo; ; genital tubercle; ; ventricular zone; ; neural tube; ; epiblast; ; ganglionic eminence; ; yolk sac; ; internal carotid artery; ; external carotid artery;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	transferase activity; nucleotide binding; protein kinase activity; mitogen-activated protein kinase binding; kinase activity; protein binding; ATP binding; protein serine/threonine kinase activity; MAP kinase activity;
Cellular component	cytoplasm; cytosol; PML body; nucleoplasm; nucleus;
Biological process	cellular response to transforming growth factor beta stimulus; negative regulation of endothelial cell apoptotic process; cell differentiation; phosphorylation; negative regulation of ERK5 cascade; cellular response to laminar fluid shear stress; positive regulation of transcription from RNA polymerase II promoter in response to stress; cellular response to growth factor stimulus; negative regulation of apoptotic process; regulation of angiogenesis; negative regulation of response to cytokine stimulus; protein phosphorylation; negative regulation of MAP kinase activity; peptidyl-serine phosphorylation; cell cycle; negative regulation of cyclic-nucleotide phosphodiesterase activity; negative regulation of heterotypic cell-cell adhesion; negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; negative regulation of inflammatory response; cAMP-mediated signaling; signal transduction; positive regulation of transcription by RNA polymerase II; cellular response to hydrogen peroxide; MAPK cascade; axon guidance; negative regulation of calcineurin-NFAT signaling cascade; regulation of gene expression; intracellular signal transduction; cellular response to organic substance;
	Sources:Amigo / QuickGO
Orthologs
	5598
	23939
	ENSG00000166484
	ENSMUSG00000001034
	Q13164
	Q9WVS8
	NM_002749; NM_139032; NM_139033; NM_139034
NM_001291033; NM_001291034; NM_001291035; NM_001291036; NM_001291037;
	NM_011841; NM_001361989
	NP_002740; NP_620601; NP_620602; NP_620603
NP_001277962; NP_001277963; NP_001277964; NP_001277965; NP_001277966;
	NP_035971; NP_001348918
	Wikidata
View/Edit Human	View/Edit Mouse

Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.^[5]^[6]

Function

MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. MAPK7 is also referred to as ERK5 or BMK (Big MAPK) due to its large size which is around double that of other ERKs. This kinase is specifically activated by mitogen-activated protein kinase kinase 5 (MAP2K5/MEK5). It is involved in the downstream signaling processes of various receptor molecules including receptor tyrosine kinases, and G protein-coupled receptors. In response to extracellular signals, this kinase translocates to the cell nucleus, where it regulates gene expression by phosphorylating, and activating different transcription factors. Four alternatively spliced transcript variants of this gene encoding two distinct isoforms have been reported.^[7]

MAPK7 is also critical for cardiovascular development ^[8] and is essential for endothelial cell function.^[9]^[10]

Interactions

MAPK7 has been shown to interact with:

ERK5 (= MAPK7) Inhibitors

XMD8-92 was one of the first described ERK5 inhibitors and was used in several pharmacological studies as tool compound. However, XMD8-92 hits BRD4 as an off-target^[17] leading to false or inconclusive results. Consequently, ERK5 inhibitors with improved selectivity (void of the BRD4 off-target effect) such as AX15836^[17] and BAY-885^[18] were developed and should preferably be used for future pharmacological studies. BAY-885 fulfils the quality criteria for a 'Donated Chemical Probe' as defined by the Structural Genomics Consortium.^[19] In 2020, it was demonstrated that ATP-competitive inhibitors paradoxically activate ERK5 signalling.^[20] A recent review discussed the modulation of ERK5 activity as a therapeutic anti-cancer strategy.^[21]

ERK5 (= MAPK7) Degrader

Based on a close analog of the ERK5 inhibitor BAY-885^[18] the Proteolysis Targeting Chimera^[22] (PROTAC) INY-06-061^[23] was developed which allows to compare the phenotypes resulting from ERK5 inhibition versus degradation.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000166484 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000001034 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Purandare SM, Lee JD, Patel PI (March 1999). "Assignment of big MAP kinase (PRKM7) to human chromosome 17 band p11.2 with somatic cell hybrids". Cytogenetics and Cell Genetics. 83 (3–4): 258–259. doi:10.1159/000015199. PMID 10072598. S2CID 31186896.
^ ^a ^b 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): 12665–12669. doi:10.1074/jbc.270.21.12665. PMID 7759517.
^ "Entrez Gene: MAPK7 mitogen-activated protein kinase 7".
^ Hayashi M, Lee JD (December 2004). "Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice". Journal of Molecular Medicine. 82 (12): 800–808. doi:10.1007/s00109-004-0602-8. PMID 15517128. S2CID 8499230.
^ Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ (December 2009). "ERK5 and the regulation of endothelial cell function". Biochemical Society Transactions. 37 (Pt 6): 1254–1259. doi:10.1042/BST0371254. PMID 19909257.
^ Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ (September 2010). "ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells". Journal of Cell Science. 123 (Pt 18): 3189–3200. doi:10.1242/jcs.072801. PMID 20736307.
^ English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MH (October 1999). "Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control". The Journal of Biological Chemistry. 274 (44): 31588–31592. doi:10.1074/jbc.274.44.31588. PMID 10531364.
^ Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, et al. (May 2003). "Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation". The Journal of Biological Chemistry. 278 (20): 18682–18688. doi:10.1074/jbc.M213283200. PMID 12637502.
^ ^a ^b Yang CC, Ornatsky OI, McDermott JC, Cruz TF, Prody CA (October 1998). "Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1". Nucleic Acids Research. 26 (20): 4771–4777. doi:10.1093/nar/26.20.4771. PMC 147902. PMID 9753748.
^ Buschbeck M, Eickhoff J, Sommer MN, Ullrich A (August 2002). "Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway". The Journal of Biological Chemistry. 277 (33): 29503–29509. doi:10.1074/jbc.M202149200. PMID 12042304.
^ Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, et al. (March 2001). "BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase". The Journal of Biological Chemistry. 276 (12): 8631–8634. doi:10.1074/jbc.C000838200. PMID 11254654.
^ Zheng Q, Yin G, Yan C, Cavet M, Berk BC (March 2004). "14-3-3beta binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) and regulates BMK1 function". The Journal of Biological Chemistry. 279 (10): 8787–8791. doi:10.1074/jbc.M310212200. PMID 14679215.
^ ^a ^b Lin EC, Amantea CM, Nomanbhoy TK, Weissig H, Ishiyama J, Hu Y, et al. (October 2016). "ERK5 kinase activity is dispensable for cellular immune response and proliferation". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): 11865–11870. Bibcode:2016PNAS..11311865L. doi:10.1073/pnas.1609019113. PMC 5081620. PMID 27679845.
^ ^a ^b Nguyen D, Lemos C, Wortmann L, Eis K, Holton SJ, Boemer U, et al. (January 2019). "Discovery and Characterization of the Potent and Highly Selective (Piperidin-4-yl)pyrido[3,2- d]pyrimidine Based in Vitro Probe BAY-885 for the Kinase ERK5". Journal of Medicinal Chemistry. 62 (2): 928–940. doi:10.1021/acs.jmedchem.8b01606. PMID 30563338. S2CID 56478089.
^ "Donated chemical probes". SGC. 2018-06-12. Retrieved 2023-07-26.
^ Cook SJ, Tucker JA, Lochhead PA (October 2020). "Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…". Biochemical Society Transactions. 48 (5): 1859–1875. doi:10.1042/BST20190338. PMC 7609025. PMID 32915196.
^ Miller DC, Harnor SJ, Martin MP, Noble RA, Wedge SR, Cano C (April 2023). "Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy". Journal of Medicinal Chemistry. 66 (7): 4491–4502. doi:10.1021/acs.jmedchem.3c00072. PMC 10108346. PMID 37002872.
^ Luh LM, Scheib U, Juenemann K, Wortmann L, Brands M, Cromm PM (September 2020). "Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective". Angewandte Chemie. 59 (36): 15448–15466. Bibcode:2020ACIE...5915448L. doi:10.1002/anie.202004310. PMC 7496094. PMID 32428344.
^ You I, Donovan KA, Krupnick NM, Boghossian AS, Rees MG, Ronan MM, et al. (November 2022). "Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation". Cell Chemical Biology. 29 (11): 1630–1638.e7. doi:10.1016/j.chembiol.2022.09.004. PMC 9675722. PMID 36220104.

External links

MAP Kinase Resource Archived 2021-04-15 at the Wayback Machine.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000166484 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000001034 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10072598-5] Purandare SM, Lee JD, Patel PI (March 1999). "Assignment of big MAP kinase (PRKM7) to human chromosome 17 band p11.2 with somatic cell hybrids". Cytogenetics and Cell Genetics. 83 (3–4): 258–259. doi:10.1159/000015199. PMID 10072598. S2CID 31186896.

[pmid7759517-6] 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): 12665–12669. doi:10.1074/jbc.270.21.12665. PMID 7759517.

[entrez-7] "Entrez Gene: MAPK7 mitogen-activated protein kinase 7".

[pmid15517128-8] Hayashi M, Lee JD (December 2004). "Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice". Journal of Molecular Medicine. 82 (12): 800–808. doi:10.1007/s00109-004-0602-8. PMID 15517128. S2CID 8499230.

[pmid19909257-9] Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ (December 2009). "ERK5 and the regulation of endothelial cell function". Biochemical Society Transactions. 37 (Pt 6): 1254–1259. doi:10.1042/BST0371254. PMID 19909257.

[pmid20736307-10] Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ (September 2010). "ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells". Journal of Cell Science. 123 (Pt 18): 3189–3200. doi:10.1242/jcs.072801. PMID 20736307.

[pmid10531364-11] English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MH (October 1999). "Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control". The Journal of Biological Chemistry. 274 (44): 31588–31592. doi:10.1074/jbc.274.44.31588. PMID 10531364.

[pmid12637502-12] Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, et al. (May 2003). "Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation". The Journal of Biological Chemistry. 278 (20): 18682–18688. doi:10.1074/jbc.M213283200. PMID 12637502.

[pmid9753748-13] Yang CC, Ornatsky OI, McDermott JC, Cruz TF, Prody CA (October 1998). "Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1". Nucleic Acids Research. 26 (20): 4771–4777. doi:10.1093/nar/26.20.4771. PMC 147902. PMID 9753748.

[pmid12042304-14] Buschbeck M, Eickhoff J, Sommer MN, Ullrich A (August 2002). "Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway". The Journal of Biological Chemistry. 277 (33): 29503–29509. doi:10.1074/jbc.M202149200. PMID 12042304.

[pmid11254654-15] Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, et al. (March 2001). "BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase". The Journal of Biological Chemistry. 276 (12): 8631–8634. doi:10.1074/jbc.C000838200. PMID 11254654.

[pmid14679215-16] Zheng Q, Yin G, Yan C, Cavet M, Berk BC (March 2004). "14-3-3beta binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) and regulates BMK1 function". The Journal of Biological Chemistry. 279 (10): 8787–8791. doi:10.1074/jbc.M310212200. PMID 14679215.

[Lin_2016-17] Lin EC, Amantea CM, Nomanbhoy TK, Weissig H, Ishiyama J, Hu Y, et al. (October 2016). "ERK5 kinase activity is dispensable for cellular immune response and proliferation". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): 11865–11870. Bibcode:2016PNAS..11311865L. doi:10.1073/pnas.1609019113. PMC 5081620. PMID 27679845.

[Nguyen_2019-18] Nguyen D, Lemos C, Wortmann L, Eis K, Holton SJ, Boemer U, et al. (January 2019). "Discovery and Characterization of the Potent and Highly Selective (Piperidin-4-yl)pyrido[3,2- d]pyrimidine Based in Vitro Probe BAY-885 for the Kinase ERK5". Journal of Medicinal Chemistry. 62 (2): 928–940. doi:10.1021/acs.jmedchem.8b01606. PMID 30563338. S2CID 56478089.

[19] "Donated chemical probes". SGC. 2018-06-12. Retrieved 2023-07-26.

[pmid32915196-20] Cook SJ, Tucker JA, Lochhead PA (October 2020). "Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…". Biochemical Society Transactions. 48 (5): 1859–1875. doi:10.1042/BST20190338. PMC 7609025. PMID 32915196.

[21] Miller DC, Harnor SJ, Martin MP, Noble RA, Wedge SR, Cano C (April 2023). "Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy". Journal of Medicinal Chemistry. 66 (7): 4491–4502. doi:10.1021/acs.jmedchem.3c00072. PMC 10108346. PMID 37002872.

[22] Luh LM, Scheib U, Juenemann K, Wortmann L, Brands M, Cromm PM (September 2020). "Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective". Angewandte Chemie. 59 (36): 15448–15466. Bibcode:2020ACIE...5915448L. doi:10.1002/anie.202004310. PMC 7496094. PMID 32428344.

[23] You I, Donovan KA, Krupnick NM, Boghossian AS, Rees MG, Ronan MM, et al. (November 2022). "Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation". Cell Chemical Biology. 29 (11): 1630–1638.e7. doi:10.1016/j.chembiol.2022.09.004. PMC 9675722. PMID 36220104.

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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Media Pages

Timelines

Articles

Notes collections

Notes

Notes

Days in Chronicle

MAPK7

Function

Interactions

ERK5 (= MAPK7) Inhibitors

ERK5 (= MAPK7) Degrader

References

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External links

Add your contribution

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