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

FEBS Lett. 2003 Aug 28;550(1-3):51-6. doi: 10.1016/s0014-5793(03)00816-0.


The mammalian target of rapamycin (mTOR) promotes increased protein synthesis required for cell growth. It has been suggested that phosphatidic acid, produced upon activation of phospholipase D (PLD), is a common mediator of growth factor activation of mTOR signaling. We used Rat-1 fibroblasts expressing the alpha(1A) adrenergic receptor to study if this G(q)-coupled receptor uses PLD to regulate mTOR signaling. Phenylephrine (PE) stimulation of the alpha(1A) adrenergic receptor induced mTOR autophosphorylation at Ser2481 and phosphorylation of two mTOR effectors, 4E-BP1 and p70 S6 kinase. These PE-induced phosphorylations were greatly reduced in cells depleted of intracellular Ca(2+). PE activation of PLD was also inhibited in Ca(2+)-depleted cells. Incubation of cells with 1-butanol to inhibit PLD signaling attenuated PE-induced phosphorylation of mTOR, 4E-BP1 and p70 S6 kinase. By contrast, platelet-derived growth factor (PDGF)-induced phosphorylation of these proteins was not blocked by Ca(2+) depletion or 1-butanol treatment. These results suggest that the alpha(1A) adrenergic receptor promotes mTOR signaling via a pathway that requires an increase in intracellular Ca(2+) and activation of PLD. The PDGF receptor, by contrast, appears to activate mTOR by a distinct pathway that does not require Ca(2+) or PLD.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Butanol / pharmacology
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Calcium / metabolism*
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Phenylephrine / pharmacology
  • Phospholipase D / genetics
  • Phospholipase D / metabolism*
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Kinase C / drug effects
  • Protein Kinase C / metabolism
  • Protein Kinases / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Rats
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases


  • Adra1a protein, rat
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-Agonists
  • Carrier Proteins
  • Eif4ebp1 protein, rat
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Platelet-Derived Growth Factor
  • Receptors, Adrenergic, alpha-1
  • Phenylephrine
  • 1-Butanol
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Receptors, Platelet-Derived Growth Factor
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Protein Kinase C
  • Phospholipase D
  • Calcium