MAPK7 explained

See main article: Mitogen-activated protein kinase.

Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.^{[1] [2]}

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. 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.^[3]

MAPK7 is also critical for cardiovascular development ^[4] and is essential for endothelial cell function.^{[5] [6]}

Interactions

MAPK7 has been shown to interact with:

• C-Raf,^[7]
• Gap junction protein, alpha 1^[8]
• MAP2K5,
• MEF2C,^[9]
• MEF2D,^[9]
• PTPRR,^[10]
• SGK,^[11] and
• YWHAB.^[12]

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^[13] leading to false or inconclusive results. Consequently, ERK5 inhibitors with improved selectivity (void of the BRD4 off-target effect) such as AX15836 and BAY-885^[14] 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.^[15] In 2020, it was demonstrated that ATP-competitive inhibitors paradoxically activate ERK5 signalling.^[16] A recent review discussed the modulation of ERK5 activity as a therapeutic anti-cancer strategy.^[17]

ERK5 (= MAPK7) Degrader

Based on a close analog of the ERK5 inhibitor BAY-885 the Proteolysis Targeting Chimera^[18] (PROTAC) INY-06-061^[19] was developed which allows to compare the phenotypes resulting from ERK5 inhibition versus degradation.

Further reading

• Lee JD, Ulevitch RJ, Han J . Primary structure of BMK1: a new mammalian map kinase . Biochemical and Biophysical Research Communications . 213 . 2 . 715–724 . August 1995 . 7646528 . 10.1006/bbrc.1995.2189 .
• Warn-Cramer BJ, Lampe PD, Kurata WE, Kanemitsu MY, Loo LW, Eckhart W, Lau AF . Characterization of the mitogen-activated protein kinase phosphorylation sites on the connexin-43 gap junction protein . The Journal of Biological Chemistry . 271 . 7 . 3779–3786 . February 1996 . 8631994 . 10.1074/jbc.271.7.3779 . free .
• Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD . BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C . The EMBO Journal . 16 . 23 . 7054–7066 . December 1997 . 9384584 . 1170308 . 10.1093/emboj/16.23.7054 .
• English JM, Pearson G, Baer R, Cobb MH . Identification of substrates and regulators of the mitogen-activated protein kinase ERK5 using chimeric protein kinases . The Journal of Biological Chemistry . 273 . 7 . 3854–3860 . February 1998 . 9461566 . 10.1074/jbc.273.7.3854 . free .
• Grunwald ME, Yu WP, Yu HH, Yau KW . Identification of a domain on the beta-subunit of the rod cGMP-gated cation channel that mediates inhibition by calcium-calmodulin . The Journal of Biological Chemistry . 273 . 15 . 9148–9157 . April 1998 . 9535905 . 10.1074/jbc.273.15.9148 . free .
• Warn-Cramer BJ, Cottrell GT, Burt JM, Lau AF . Regulation of connexin-43 gap junctional intercellular communication by mitogen-activated protein kinase . The Journal of Biological Chemistry . 273 . 15 . 9188–9196 . April 1998 . 9535909 . 10.1074/jbc.273.15.9188 . free .
• Yang CC, Ornatsky OI, McDermott JC, Cruz TF, Prody CA . Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1 . Nucleic Acids Research . 26 . 20 . 4771–4777 . October 1998 . 9753748 . 147902 . 10.1093/nar/26.20.4771 .
• Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD . Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor . Nature . 395 . 6703 . 713–716 . October 1998 . 9790194 . 10.1038/27234 . 204997780 . 1998Natur.395..713K .
• Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J . 6 . Regulation of the MEF2 family of transcription factors by p38 . Molecular and Cellular Biology . 19 . 1 . 21–30 . January 1999 . 9858528 . 83862 . 10.1128/mcb.19.1.21 .
• Kamakura S, Moriguchi T, Nishida E . Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus . The Journal of Biological Chemistry . 274 . 37 . 26563–26571 . September 1999 . 10473620 . 10.1074/jbc.274.37.26563 . free .
• English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MH . Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control . The Journal of Biological Chemistry . 274 . 44 . 31588–31592 . October 1999 . 10531364 . 10.1074/jbc.274.44.31588 . free .
• Fukuhara S, Marinissen MJ, Chiariello M, Gutkind JS . Signaling from G protein-coupled receptors to ERK5/Big MAPK 1 involves Galpha q and Galpha 12/13 families of heterotrimeric G proteins. Evidence for the existence of a novel Ras AND Rho-independent pathway . The Journal of Biological Chemistry . 275 . 28 . 21730–21736 . July 2000 . 10781600 . 10.1074/jbc.M002410200 . free .
• Kato Y, Zhao M, Morikawa A, Sugiyama T, Chakravortty D, Koide N, Yoshida T, Tapping RI, Yang Y, Yokochi T, Lee JD . 6 . Big mitogen-activated kinase regulates multiple members of the MEF2 protein family . The Journal of Biological Chemistry . 275 . 24 . 18534–18540 . June 2000 . 10849446 . 10.1074/jbc.M001573200 . free .
• Yan C, Luo H, Lee JD, Abe J, Berk BC . Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains . The Journal of Biological Chemistry . 276 . 14 . 10870–10878 . April 2001 . 11139578 . 10.1074/jbc.M009286200 . free .
• Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, Lee JD . 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 . March 2001 . 11254654 . 10.1074/jbc.C000838200 . free .
• Dong F, Gutkind JS, Larner AC . Granulocyte colony-stimulating factor induces ERK5 activation, which is differentially regulated by protein-tyrosine kinases and protein kinase C. Regulation of cell proliferation and survival . The Journal of Biological Chemistry . 276 . 14 . 10811–10816 . April 2001 . 11278431 . 10.1074/jbc.M008748200 . free .
• Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA . Neurotrophins use the Erk5 pathway to mediate a retrograde survival response . Nature Neuroscience . 4 . 10 . 981–988 . October 2001 . 11544482 . 10.1038/nn720 . 3164934 .
• Esparís-Ogando A, Díaz-Rodríguez E, Montero JC, Yuste L, Crespo P, Pandiella A . Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2 . Molecular and Cellular Biology . 22 . 1 . 270–285 . January 2002 . 11739740 . 134212 . 10.1128/MCB.22.1.270-285.2002 .

External links

• MAP Kinase Resource .

Notes and References

1. Purandare SM, Lee JD, Patel PI . 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 . March 1999 . 10072598 . 10.1159/000015199 . 31186896 .
2. Zhou G, Bao ZQ, Dixon JE . Components of a new human protein kinase signal transduction pathway . The Journal of Biological Chemistry . 270 . 21 . 12665–12669 . May 1995 . 7759517 . 10.1074/jbc.270.21.12665 . free .
3. Web site: Entrez Gene: MAPK7 mitogen-activated protein kinase 7.
4. Hayashi M, Lee JD . Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice . Journal of Molecular Medicine . 82 . 12 . 800–808 . December 2004 . 15517128 . 10.1007/s00109-004-0602-8 . 8499230 .
5. Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ . ERK5 and the regulation of endothelial cell function . Biochemical Society Transactions . 37 . Pt 6 . 1254–1259 . December 2009 . 19909257 . 10.1042/BST0371254 .
6. Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ . 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 . September 2010 . 20736307 . 10.1242/jcs.072801 . free .
7. English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MH . Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control . The Journal of Biological Chemistry . 274 . 44 . 31588–31592 . October 1999 . 10531364 . 10.1074/jbc.274.44.31588 . free .
8. Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, Abe J, Yang J . 6 . 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 . May 2003 . 12637502 . 10.1074/jbc.M213283200 . free .
9. Yang CC, Ornatsky OI, McDermott JC, Cruz TF, Prody CA . Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1 . Nucleic Acids Research . 26 . 20 . 4771–4777 . October 1998 . 9753748 . 147902 . 10.1093/nar/26.20.4771 .
10. Buschbeck M, Eickhoff J, Sommer MN, Ullrich A . Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway . The Journal of Biological Chemistry . 277 . 33 . 29503–29509 . August 2002 . 12042304 . 10.1074/jbc.M202149200 . free .
11. Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, Lee JD . 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 . March 2001 . 11254654 . 10.1074/jbc.C000838200 . free .
12. Zheng Q, Yin G, Yan C, Cavet M, Berk BC . 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 . March 2004 . 14679215 . 10.1074/jbc.M310212200 . free .
13. Lin EC, Amantea CM, Nomanbhoy TK, Weissig H, Ishiyama J, Hu Y, Sidique S, Li B, Kozarich JW, Rosenblum JS . 6 . 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 . October 2016 . 27679845 . 5081620 . 10.1073/pnas.1609019113 . 2016PNAS..11311865L . free .
14. Nguyen D, Lemos C, Wortmann L, Eis K, Holton SJ, Boemer U, Moosmayer D, Eberspaecher U, Weiske J, Lechner C, Prechtl S, Suelzle D, Siegel F, Prinz F, Lesche R, Nicke B, Nowak-Reppel K, Himmel H, Mumberg D, von Nussbaum F, Nising CF, Bauser M, Haegebarth A . 6 . 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 . January 2019 . 30563338 . 10.1021/acs.jmedchem.8b01606 . 56478089 .
15. Web site: 2018-06-12 . Donated chemical probes . 2023-07-26 . SGC . en.
16. Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for… . Biochemical Society Transactions.
17. Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy . Journal of Medicinal Chemistry. 2023 . 10.1021/acs.jmedchem.3c00072 . Miller . Duncan C. . Harnor . Suzannah J. . Martin . Mathew P. . Noble . Richard A. . Wedge . Stephen R. . Cano . Celine . 66 . 7 . 4491–4502 . 37002872 . 10108346 .
18. Luh LM, Scheib U, Juenemann K, Wortmann L, Brands M, Cromm PM . Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective . Angewandte Chemie . 59 . 36 . 15448–15466 . September 2020 . 32428344 . 7496094 . 10.1002/anie.202004310 .
19. You I, Donovan KA, Krupnick NM, Boghossian AS, Rees MG, Ronan MM, Roth JA, Fischer ES, Wang ES, Gray NS . 6 . Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation . Cell Chemical Biology . 29 . 11 . 1630–1638.e7 . November 2022 . 36220104 . 10.1016/j.chembiol.2022.09.004 . 9675722 .