Stimulation of the four isoforms of receptor tyrosine kinase ErbB4, but not ErbB1, confers cardiomyocyte hypertrophy
Autor: | Brooke W. Purdue, Melissa E. Reichelt, David J. Pennisi, Enzo R. Porrello, Nicola J. Smith, Giovanna Gambarotta, Zhen Wang, Hsiu-Wen Chan, Shannon L. O'Brien, Walter G. Thomas, Tamara M. Paravicini |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Receptor ErbB-4 Receptor ErbB-3 Physiology Clinical Biochemistry cardiomyocytes cardiomyocytes epidermal growth factor receptors hypertrophy ventricular remodeling ventricular remodeling Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Growth factor receptor Epidermal growth factor Animals Humans Protein Isoforms Myocytes Cardiac Phosphorylation Neuregulin 1 Protein kinase A ERBB4 Cell Proliferation biology Chemistry Cell Biology Cell biology Alternative Splicing 030104 developmental biology 030220 oncology & carcinogenesis biology.protein epidermal growth factor receptors Neuregulin hypertrophy Signal Transduction |
Zdroj: | Journal of Cellular Physiology. 236:8160-8170 |
ISSN: | 1097-4652 0021-9541 |
Popis: | Epidermal growth factor (EGF) receptors (ErbB1-ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF-like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1-mediated hypertrophy occurred despite robust activation of extracellular-regulated kinase 1/2 (ERK) and protein kinase B. Hypertrophic responses to NRG1 were unaffected by the tyrosine kinase inhibitor (AG1478) at concentrations that are selective for ErbB1 over ErbB4. NRG1-induced cardiomyocyte enlargement was suppressed by small interfering RNA (siRNA) knockdown of ErbB4 and ErbB2, whereas ERK phosphorylation was only suppressed by ErbB4 siRNA. Four ErbB4 isoforms exist (JM-a/JM-b and CYT-1/CYT-2), generated by alternative splicing, and their expression declines postnatally and following cardiac hypertrophy. Silencing of all four isoforms in cardiomyocytes, using an ErbB4 siRNA, abrogated NRG1-induced hypertrophic promoter/reporter activity, which was rescued by coexpression of knockdown-resistant versions of the ErbB4 isoforms. Thus, ErbB4 confers cardiomyocyte hypertrophy to NRG1, and all four ErbB4 isoforms possess the capacity to mediate this effect. |
Databáze: | OpenAIRE |
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