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Journal article

Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway.

  • Fu X Department of Chemistry and Applied Biosciences, Molecular Pharmacology Unit, Swiss Federal Institute of Technology Zuerich, CH-8057 Zuerich, Switzerland.
  • Koller S
  • Abd Alla J
  • Quitterer U
  • 2013-01-31
Published in:
  • The Journal of biological chemistry. - 2013
Animals
Cell Line, Tumor
Chromatography, Liquid
Cytomegalovirus
G-Protein-Coupled Receptor Kinase 2
Gene Expression Regulation
HEK293 Cells
Heart Failure
Humans
MAP Kinase Signaling System
Mice
Mice, Transgenic
Mutation
Myocytes, Cardiac
Oligonucleotide Array Sequence Analysis
Spectrometry, Mass, Electrospray Ionization
Tandem Mass Spectrometry
Transgenes
English Inhibition of G-protein-coupled receptor kinase 2 (GRK2) is an emerging treatment option for heart failure. Because GRK2 is also indispensable for growth and development, we analyzed the impact of GRK2 inhibition on cell growth and proliferation. Inhibition of GRK2 by the dominant-negative GRK2-K220R did not affect the proliferation of cultured cells. In contrast, upon xenograft transplantation of cells into immunodeficient mice, the dominant-negative GRK2-K220R or a GRK2-specific peptide inhibitor increased tumor mass. The enhanced tumor growth upon GRK2 inhibition was attributed to the growth-promoting MAPK pathway because dual inhibition of the GRK2 and RAF-MAPK axis by the Raf kinase inhibitor protein (RKIP) did not increase tumor mass. The MAPK cascade contributed to the cardioprotective profile of GRK2 inhibition by preventing cardiomyocyte death, whereas dual inhibition of RAF/MAPK and GRK2 by RKIP induced cardiomyocyte apoptosis, cardiac dysfunction, and signs of heart failure. Thus, cardioprotective signaling induced by GRK2 inhibition is overlapping with tumor growth promotion.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/67899
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