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Sphingosine-1-phosphate-induced smooth muscle cell migration involves the mammalian target of rapamycin

William J Tanski1, Suzanne M Nicholl, Dong Kim

  • 1Division of Vascular Surgery, Vascular Biology and Therapeutics Program, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.

Journal of Vascular Surgery
|February 8, 2005
PubMed
Abstract

Insights

Rapamycin completely inhibits sphingosine-1-phosphate (S-1-P)-induced vascular smooth muscle cell (SMC) migration by targeting the mammalian target of rapamycin (mTOR) and ribosomal p70S6 kinase (p70S6K) pathway. This pathway is crucial for intimal hyperplasia development.

Area of Science:

  • Vascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Vascular smooth muscle cell (SMC) migration is a key process in intimal hyperplasia.
  • Sphingosine-1-phosphate (S-1-P), released by platelets, stimulates SMC migration.
  • The role of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K) in S-1-P-induced migration requires investigation.

Purpose of the Study:

  • To investigate the involvement of the mTOR/p70S6K pathway in S-1-P-induced SMC migration.
  • To elucidate the signaling mechanisms underlying S-1-P-mediated SMC migration.

Main Methods:

  • Rat arterial SMCs were subjected to wound healing and Boyden chamber assays.
  • Cellular responses to S-1-P were assessed with and without rapamycin treatment.
  • Western blotting analyzed the phosphorylation status of p70S6K, ERK1/2, and p38(MAPK) under various conditions, including inhibition of PI3K, Akt, p38(MAPK), and MEK1.

Main Results:

  • S-1-P significantly stimulated SMC migration, an effect completely abrogated by rapamycin.
  • Rapamycin inhibited p70S6K phosphorylation at Thr 389 and reduced ERK1/2 phosphorylation.
  • S-1-P-induced p70S6K phosphorylation was dependent on MEK1 and PI3K but independent of Akt.

Conclusions:

  • The p70S6K pathway, modulated by mTOR, is essential for S-1-P-induced SMC migration.
  • The ERK1/2 pathway is likely involved in this process.
  • S-1-P regulates p70S6K phosphorylation via a MEK1- and PI3K-dependent, Akt-independent signaling cascade.

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