Differential regulation of the phosphatidylinositol 3-kinase/Akt and p70 S6 kinase pathways by the α(1A)-adrenergic receptor in rat-1 fibroblasts

Lisa M. Ballou, Michael E. Cross, Siqi Huang, E. Michael McReynolds, Bin Xian Zhang, Richard Z. Lin

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Abstract

Phosphatidylinositol (PI) 3-kinase and its downstream effector Akt are thought to be signaling intermediates that link cell surface receptors to p70 S6 kinase. We examined the effect of a G(q)-coupled receptor on PI 3- kinase/Akt signaling and p70 S6 kinase activation using Rat-1 fibroblasts stably expressing the human α(1A)adrenergic receptor. Treatment of the cells with phenylephrine, a specific α1-adrenergic receptor agonist, activated p70 S6 kinase but did not activate PI 3-kinase or any of the three known isoforms of Akt. Furthermore, phenylephrine blocked the insulin-like growth factor-I (IGF-I)-induced activation of PI 3-kinase and the phosphorylation and activation of Akt-1. The effect of phenylephrine was not confined to signaling pathways that include insulin receptor substrate-1, as the α1- adrenergic receptor agonist also inhibited the platelet-derived growth factor-induced activation of PI 3-kinase and Akt-1. Although increasing the intracellular Ca2+ concentration with the ionophore A23187 inhibited the activation of Akt-1 by IGF-I, Ca2+ does not appear to play a role in the phenylephrine-mediated inhibition of the PI 3-kinase/Akt pathway. The differential ability of phenylephrine and IGF-I to activate Akt-1 resulted in a differential ability to protect cells from UV-induced apoptosis. These results demonstrate that activation of p70 S6 kinase by the α(1A)-adrenergic receptor in Rat-1 fibroblasts occurs in the absence of PI 3-kinase/Akt signaling. Furthermore, this receptor negatively regulates the PI 3- kinase/Akt pathway, resulting in enhanced cell death following apoptotic insult.

Original languageEnglish (US)
Pages (from-to)4803-4809
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number7
DOIs
StatePublished - Feb 18 2000

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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