Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7gene.[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. 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]
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.
^"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. PMID10072598. S2CID31186896.
^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. PMID15517128. S2CID8499230.
^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. PMID19909257.
^ abNguyen 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. PMID30563338. S2CID56478089.
Lee JD, Ulevitch RJ, Han J (August 1995). "Primary structure of BMK1: a new mammalian map kinase". Biochemical and Biophysical Research Communications. 213 (2): 715–724. doi:10.1006/bbrc.1995.2189. PMID7646528.
Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA (October 2001). "Neurotrophins use the Erk5 pathway to mediate a retrograde survival response". Nature Neuroscience. 4 (10): 981–988. doi:10.1038/nn720. PMID11544482. S2CID3164934.
