Biology:MAPK7

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Short description: Protein-coding gene in the species Homo sapiens
Main page: Biology:Mitogen-activated protein kinase
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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:


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[13] 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[14] the Proteolysis Targeting Chimera[18] (PROTAC) INY-06-061[19] was developed which allows to compare the phenotypes resulting from ERK5 inhibition versus degradation.

References

  1. ↑ "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. doi:10.1159/000015199. PMID 10072598. 
  2. ↑ 2.0 2.1 "Components of a new human protein kinase signal transduction pathway". The Journal of Biological Chemistry 270 (21): 12665–12669. May 1995. doi:10.1074/jbc.270.21.12665. PMID 7759517. 
  3. ↑ "Entrez Gene: MAPK7 mitogen-activated protein kinase 7". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5598. 
  4. ↑ "Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice". Journal of Molecular Medicine 82 (12): 800–808. December 2004. doi:10.1007/s00109-004-0602-8. PMID 15517128. 
  5. ↑ "ERK5 and the regulation of endothelial cell function". Biochemical Society Transactions 37 (Pt 6): 1254–1259. December 2009. doi:10.1042/BST0371254. PMID 19909257. 
  6. ↑ "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. doi:10.1242/jcs.072801. PMID 20736307. 
  7. ↑ "Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control". The Journal of Biological Chemistry 274 (44): 31588–31592. October 1999. doi:10.1074/jbc.274.44.31588. PMID 10531364. 
  8. ↑ "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. doi:10.1074/jbc.M213283200. PMID 12637502. 
  9. ↑ 9.0 9.1 "Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1". Nucleic Acids Research 26 (20): 4771–4777. October 1998. doi:10.1093/nar/26.20.4771. PMID 9753748. 
  10. ↑ "Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway". The Journal of Biological Chemistry 277 (33): 29503–29509. August 2002. doi:10.1074/jbc.M202149200. PMID 12042304. 
  11. ↑ "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. doi:10.1074/jbc.C000838200. PMID 11254654. 
  12. ↑ "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. doi:10.1074/jbc.M310212200. PMID 14679215. 
  13. ↑ 13.0 13.1 "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. doi:10.1073/pnas.1609019113. PMID 27679845. Bibcode: 2016PNAS..11311865L. 
  14. ↑ 14.0 14.1 "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. doi:10.1021/acs.jmedchem.8b01606. PMID 30563338. 
  15. ↑ "Donated chemical probes" (in en). 2018-06-12. https://www.thesgc.org/donated-chemical-probes. 
  16. ↑ "Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…". Biochemical Society Transactions. https://portlandpress.com/biochemsoctrans/article/48/5/1859/226398/Small-molecule-ERK5-kinase-inhibitors. 
  17. ↑ Miller, Duncan C.; Harnor, Suzannah J.; Martin, Mathew P.; Noble, Richard A.; Wedge, Stephen R.; Cano, Celine (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. PMID 37002872. 
  18. ↑ "Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective". Angewandte Chemie 59 (36): 15448–15466. September 2020. doi:10.1002/anie.202004310. PMID 32428344. 
  19. ↑ "Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation". Cell Chemical Biology 29 (11): 1630–1638.e7. November 2022. doi:10.1016/j.chembiol.2022.09.004. PMID 36220104. 

Further reading

External links



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