A1 Journal article (refereed)
STAT5b is a key effector of NRG-1/ERBB4-mediated myocardial growth (2023)

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), Article e56689. https://doi.org/10.15252/embr.202256689

JYU authors or editors

Publication details

All authors or editors: Vaparanta, Katri; Jokilammi, Anne; Paatero, Ilkka; Merilahti, Johannes A.; Heliste, Juho; Hemanthakumar, Karthik Amudhala; Kivelä, Riikka; Alitalo, Kari; Taimen, Pekka; Elenius, Klaus

Journal or series: Embo reports

ISSN: 1469-221X

eISSN: 1469-3178

Publication year: 2023

Publication date: 03/04/2023

Volume: 24

Issue number: 5

Article number: e56689

Publisher: EMBO

Publication country: Germany

Publication language: English

DOI: https://doi.org/10.15252/embr.202256689

Research data link: https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD040166

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/88066

Web address of parallel published publication (pre-print): https://www.biorxiv.org/content/10.1101/2022.10.05.510958v1

Additional information: The Mass spectrometry derived interactome data: ProteomeXchange Consortium (Deutsch et al, 2023) via the PRIDE (Perez-Riverol et al, 2022) partner repository PXD040166 (https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD040166) (https://www.ebi.ac.uk/pride/archive/projects/PXD040166).

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.

Keywords: heart; cardiac muscle cells; growth factors; genes; cell physiology; cardiomyopathies; hypertrophic cardiomyopathy

Free keywords: cardiomyocyte hyperplasia; cardiomyocyte hypertrophy; dynamin; NRG-1–ErbB pathway; signal transducer; activator of transcription

Contributing organizations

Ministry reporting: Yes

VIRTA submission year: 2023

JUFO rating: 3