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Involvement of ERK-RSK cascade in phenylephrine-induced phosphorylation of GATA4

Tao Li1, Zhiqiang Liu, Xiaoqing Hu

  • 1Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, Zhejiang, 321004, China. litao@zjnu.cn

Biochimica Et Biophysica Acta
|January 10, 2012
PubMed

Insights

Ribosomal S6 Kinase (RSK) directly phosphorylates GATA4, enhancing its activity in cardiac hypertrophy. This RSK-mediated GATA4 activation plays a key role in cardiac development and response to phenylephrine.

Area of Science:

  • Cardiovascular Biology
  • Molecular Signaling
  • Gene Regulation

Background:

  • GATA4 is a critical regulator of cardiac development and hypertrophy.
  • Mitogen-activated protein kinase (MAPK) pathways activate GATA4 through phosphorylation.
  • MSK (mitogen- and stress-activated protein kinase) and RSK (ribosomal S6 kinase) are key kinases downstream of MAPK.

Purpose of the Study:

  • To investigate the roles of MSK and RSK in GATA4 activation and cardiac hypertrophy.
  • To elucidate the specific mechanisms by which RSK influences GATA4 activity.
  • To determine the impact of MSK and RSK on phenylephrine-induced cardiac responses.

Main Methods:

  • Overexpression of RSK2 and MSK1 in cardiac cells.
  • Analysis of GATA4 phosphorylation at Ser261 and Ser105.
  • Assessment of GATA4 transcriptional and DNA binding activity.
  • Investigation of GATA4 interactions with NKX2.5 and p300.
  • Inhibition of RSK using the small molecule SL0101.
  • Phenylephrine treatment of cardiomyocytes.

Main Results:

  • RSK2 overexpression significantly increased GATA4 phosphorylation at Ser261, enhancing its transcriptional and DNA binding activity.
  • RSK-dependent GATA4 phosphorylation promoted interactions with NKX2.5 and p300.
  • Phenylephrine treatment induced sequential phosphorylation of the ERK-RSK-GATA4 cascade and nuclear RSK accumulation.
  • RSK inhibition by SL0101 blocked GATA4 phosphorylation and repressed fetal cardiac gene expression.
  • MSK1 overexpression increased GATA4 expression but did not directly affect its phosphorylation.

Conclusions:

  • The ERK-RSK cascade mediates dual phosphorylation of GATA4.
  • RSK plays a critical role in phenylephrine-induced cardiac hypertrophy by activating GATA4.
  • MSK and RSK exhibit distinct roles in the cardiac hypertrophic response.

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