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ERK5 kinase activity is dispensable for cellular immune response and proliferation
- Publication Year :
- 2016
- Publisher :
- National Academy of Sciences, 2016.
-
Abstract
- Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cell Survival
Gene Expression
Biology
03 medical and health sciences
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
0302 clinical medicine
Human Umbilical Vein Endothelial Cells
Animals
Humans
Kinase activity
Phosphorylation
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 7
Cell Proliferation
Inflammation
Immunity, Cellular
Multidisciplinary
Molecular Structure
Kinase
Gene Expression Profiling
Neurogenesis
Biological Sciences
Phenotype
Small molecule
Cell biology
Bromodomain
Enzyme Activation
030104 developmental biology
Protein kinase domain
Biochemistry
Gene Expression Regulation
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Cytokines
Inflammation Mediators
Transcriptome
Biomarkers
HeLa Cells
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....1fa0e539b27866c3e1d8419d25b4f8e3