MAPK7

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.

MAPK7 is also critical for cardiovascular development and is essential for endothelial cell function.

Interactions

MAPK7 has been shown to interact with:

• C-Raf,
• Gap junction protein, alpha 1
• MAP2K5,
• MEF2C,
• MEF2D,
• PTPRR,
• SGK, and
• YWHAB.

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 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 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. In 2020, it was demonstrated that ATP-competitive inhibitors paradoxically activate ERK5 signalling. A recent review discussed the modulation of ERK5 activity as a therapeutic anti-cancer strategy.

ERK5 (= MAPK7) Degrader

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

References

References

1. (March 1999). "Assignment of big MAP kinase (PRKM7) to human chromosome 17 band p11.2 with somatic cell hybrids". Cytogenetics and Cell Genetics.
2. (May 1995). "Components of a new human protein kinase signal transduction pathway". The Journal of Biological Chemistry.
3. "Entrez Gene: MAPK7 mitogen-activated protein kinase 7".
4. (December 2004). "Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice". Journal of Molecular Medicine.
5. (December 2009). "ERK5 and the regulation of endothelial cell function". Biochemical Society Transactions.
6. (September 2010). "ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells". Journal of Cell Science.
7. (October 1999). "Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control". The Journal of Biological Chemistry.
8. (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.
9. (October 1998). "Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1". Nucleic Acids Research.
10. (August 2002). "Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway". The Journal of Biological Chemistry.
11. (March 2001). "BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase". The Journal of Biological Chemistry.
12. (March 2004). "14-3-3beta binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) and regulates BMK1 function". The Journal of Biological Chemistry.
13. (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.
14. (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.
15. (2018-06-12). "Donated chemical probes".
16. (October 2020). "Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…". Biochemical Society Transactions.
17. (April 2023). "Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy". Journal of Medicinal Chemistry.
18. (September 2020). "Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective". Angewandte Chemie.
19. (November 2022). "Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation". Cell Chemical Biology.