PUBLICATION
NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart
- Authors
- Müller, M., Eghbalian, R., Boeckel, J.N., Frese, K.S., Haas, J., Kayvanpour, E., Sedaghat-Hamedani, F., Lackner, M.K., Tugrul, O.F., Ruppert, T., Tappu, R., Martins Bordalo, D., Kneuer, J.M., Piekarek, A., Herch, S., Schudy, S., Keller, A., Grammes, N., Bischof, C., Klinke, A., Cardoso-Moreira, M., Kaessmann, H., Katus, H.A., Frey, N., Steinmetz, L.M., Meder, B.
- ID
- ZDB-PUB-221022-1
- Date
- 2022
- Source
- Nature communications 13: 6209 (Journal)
- Registered Authors
- Frese, Karen, Meder, Benjamin
- Keywords
- none
- MeSH Terms
-
- Actins*/metabolism
- Animals
- Calcium/metabolism
- Humans
- Myosin Light Chains*/metabolism
- NIMA-Related Kinases/genetics
- NIMA-Related Kinases/metabolism
- Phosphorylation
- Protein Kinases/metabolism
- Zebrafish/metabolism
- PubMed
- 36266340 Full text @ Nat. Commun.
Citation
Müller, M., Eghbalian, R., Boeckel, J.N., Frese, K.S., Haas, J., Kayvanpour, E., Sedaghat-Hamedani, F., Lackner, M.K., Tugrul, O.F., Ruppert, T., Tappu, R., Martins Bordalo, D., Kneuer, J.M., Piekarek, A., Herch, S., Schudy, S., Keller, A., Grammes, N., Bischof, C., Klinke, A., Cardoso-Moreira, M., Kaessmann, H., Katus, H.A., Frey, N., Steinmetz, L.M., Meder, B. (2022) NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart. Nature communications. 13:6209.
Abstract
To adapt to changing hemodynamic demands, regulatory mechanisms modulate actin-myosin-kinetics by calcium-dependent and -independent mechanisms. We investigate the posttranslational modification of human essential myosin light chain (ELC) and identify NIMA-related kinase 9 (NEK9) to interact with ELC. NEK9 is highly expressed in the heart and the interaction with ELC is calcium-dependent. Silencing of NEK9 results in blunting of calcium-dependent ELC-phosphorylation. CRISPR/Cas9-mediated disruption of NEK9 leads to cardiomyopathy in zebrafish. Binding to ELC is mediated via the protein kinase domain of NEK9. A causal relationship between NEK9 activity and ELC-phosphorylation is demonstrated by genetic sensitizing in-vivo. Finally, we observe significantly upregulated ELC-phosphorylation in dilated cardiomyopathy patients and provide a unique map of human ELC-phosphorylation-sites. In summary, NEK9-mediated ELC-phosphorylation is a calcium-dependent regulatory system mediating cardiac contraction and inotropy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping