PUBLICATION
STAT5b is a key effector of NRG-1/ERBB4-mediated myocardial growth
- Authors
- Vaparanta, K., Jokilammi, A., Paatero, I., Merilahti, J.A., Heliste, J., Hemanthakumar, K.A., Kivelä, R., Alitalo, K., Taimen, P., Elenius, K.
- ID
- ZDB-PUB-230404-54
- Date
- 2023
- Source
- EMBO reports 24(5): e56689 (Journal)
- Registered Authors
- Paatero, Ilkka
- Keywords
- NRG-1-ErbB pathway, cardiomyocyte hyperplasia, cardiomyocyte hypertrophy, dynamin, signal transducer and activator of transcription
- MeSH Terms
-
- Animals
- Dynamin II*/metabolism
- Humans
- Hypertrophy
- Mice
- Neuregulin-1*/genetics
- Neuregulin-1*/metabolism
- Neuregulin-1*/pharmacology
- Receptor, ErbB-4/genetics
- Receptor, ErbB-4/metabolism
- STAT5 Transcription Factor/genetics
- STAT5 Transcription Factor/metabolism
- Zebrafish/metabolism
- PubMed
- 37009825 Full text @ EMBO Rep.
Citation
Vaparanta, K., Jokilammi, A., Paatero, I., Merilahti, J.A., Heliste, J., Hemanthakumar, K.A., Kivelä, R., Alitalo, K., Taimen, P., Elenius, K. (2023) STAT5b is a key effector of NRG-1/ERBB4-mediated myocardial growth. EMBO reports. 24(5):e56689.
Abstract
The growth factor Neuregulin-1 (NRG-1) regulates myocardial growth and is currently under clinical investigation as a treatment for heart failure. Here, we demonstrate in several in vitro and in vivo models that STAT5b mediates NRG-1/EBBB4-stimulated cardiomyocyte growth. Genetic and chemical disruption of the NRG-1/ERBB4 pathway reduces STAT5b activation and transcription of STAT5b target genes Igf1, Myc, and Cdkn1a in murine cardiomyocytes. Loss of Stat5b also ablates NRG-1-induced cardiomyocyte hypertrophy. Dynamin-2 is shown to control the cell surface localization of ERBB4 and chemical inhibition of Dynamin-2 downregulates STAT5b activation and cardiomyocyte hypertrophy. In zebrafish embryos, Stat5 is activated during NRG-1-induced hyperplastic myocardial growth, and chemical inhibition of the Nrg-1/Erbb4 pathway or Dynamin-2 leads to loss of myocardial growth and Stat5 activation. Moreover, CRISPR/Cas9-mediated knockdown of stat5b results in reduced myocardial growth and cardiac function. Finally, the NRG-1/ERBB4/STAT5b signaling pathway is differentially regulated at mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to control human subjects, consistent with a role of the NRG-1/ERBB4/STAT5b pathway in myocardial growth.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping