Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''MAPK7''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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 receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

s. In response to extracellular signals, this kinase translocates to the cell nucleus, where it regulates gene expression by phosphorylating, and activating different

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

s. 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 RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is genetic code, encoded by the ''RAF1'' gene. The c-Raf protein is part of the MAPK/ERK pathway, E ...

, * 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

External links