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]
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]
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 ERK s. 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]
MAPK7 has been shown to interact with:
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]
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.
