Ca(2+)- and phospholipase D-dependent and -independent pathways activate mTOR signaling

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Lisa M Ballou1, Ya-Ping Jiang, Guangwei Du

  • 1Department of Medicine, Division of Hematology, Stony Brook University, Stony Brook, NY 11794-8151, USA.

FEBS Letters
|August 26, 2003
PubMed

Insights

The alpha(1A) adrenergic receptor signals through calcium and phospholipase D (PLD) to activate mammalian target of rapamycin (mTOR) signaling. This pathway differs from platelet-derived growth factor (PDGF) signaling, which does not require these components.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Biochemistry

Background:

  • Mammalian target of rapamycin (mTOR) regulates protein synthesis and cell growth.
  • Phosphatidic acid, generated by phospholipase D (PLD), is a proposed mediator of mTOR activation.
  • G(q)-coupled receptors, like the alpha(1A) adrenergic receptor, can influence cell growth pathways.

Purpose of the Study:

  • To investigate if the alpha(1A) adrenergic receptor utilizes phospholipase D (PLD) to regulate mTOR signaling.
  • To determine the role of intracellular calcium (Ca2+) in alpha(1A) adrenergic receptor-mediated mTOR activation.
  • To compare the mTOR signaling pathway activated by the alpha(1A) adrenergic receptor with that of the platelet-derived growth factor (PDGF) receptor.

Main Methods:

  • Utilized Rat-1 fibroblasts expressing the alpha(1A) adrenergic receptor.
  • Stimulated cells with phenylephrine (PE) and platelet-derived growth factor (PDGF).
  • Assessed mTOR, 4E-BP1, and p70 S6 kinase phosphorylation.
  • Manipulated intracellular calcium levels and inhibited PLD activity using 1-butanol.

Main Results:

  • Phenylephrine (PE) stimulation induced mTOR, 4E-BP1, and p70 S6 kinase phosphorylation.
  • PE-induced signaling was significantly reduced in calcium-depleted cells and by PLD inhibition.
  • Platelet-derived growth factor (PDGF)-induced phosphorylation was unaffected by calcium depletion or PLD inhibition.

Conclusions:

  • The alpha(1A) adrenergic receptor activates mTOR signaling through a pathway dependent on intracellular calcium and PLD.
  • This pathway is distinct from the mTOR activation mechanism employed by the PDGF receptor.
  • These findings elucidate a novel signaling cascade for G(q)-coupled receptor-mediated cell growth regulation.

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