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RGD-containing peptides activate S6K1 through beta3 integrin in adult cardiac muscle cells

Sundaravadivel Balasubramanian1, Dhandapani Kuppuswamy

  • 1Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425-2221, USA.

The Journal of Biological Chemistry
|August 12, 2003
PubMed

Insights

Integrin-interacting Arg-Gly-Asp (RGD) peptides activate p70S6 kinase (S6K1) in feline cardiomyocytes. This activation, mediated by beta3 integrin and involving endocytosis, may contribute to cardiac hypertrophy.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Integrin Biology

Background:

  • p70S6 kinase (S6K1) is crucial for cell growth and activated during cardiac hypertrophy.
  • Integrin activation is also implicated in cardiac hypertrophy, prompting investigation into its role in S6K1 activation.

Purpose of the Study:

  • To determine if integrins contribute to the activation of p70S6 kinase (S6K1) in cardiomyocytes.
  • To elucidate the specific integrin subtypes and signaling pathways involved in RGD-induced S6K1 activation.

Main Methods:

  • Utilized adult feline cardiomyocytes treated with Arg-Gly-Asp (RGD) peptides.
  • Assessed S6K1 activation via band shifting, kinase activity, and phosphorylation.
  • Employed blocking antibodies, dominant-negative constructs, specific inhibitors, and fluorescently labeled peptides to investigate integrin function, signaling pathways, and endocytosis.

Main Results:

  • RGD peptides activated S6K1, evidenced by increased phosphorylation and kinase activity.
  • Beta3 integrin, not beta1, mediated RGD-induced S6K1 activation, independent of focal adhesion complexes.
  • S6K1 activation involved mammalian target of rapamycin (mTOR), MEK/ERK, and phosphatidylinositol 3-kinase pathways, but not protein kinase C or c-Raf.
  • RGD peptide internalization into endocytic vesicles was observed, and endocytic inhibitors reduced S6K1 activation.

Conclusions:

  • RGD interaction with beta3 integrin triggers specific signaling pathways for S6K1 activation in cardiomyocytes.
  • Subsequent endocytosis of the RGD-integrin complex is critical for this activation process.
  • This integrin-mediated S6K1 activation pathway may play a role in hypertrophic growth and myocardial remodeling.

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