DIFFERENTIAL REGULATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE/AKT AND P70S6 KINASE PATHWAYS BY THE α1A ADRENERGIC RECEPTOR IN RAT-1 FIBROBLAST
Authors: Lisa M. Ballou, Michael E. Cross, Siqi Huang, E. Michael McReynolds, Bin-Xian Zhang and Richard Z. Lin*
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
Presenter: Richard Lin, M.D.
Assistant Professor, Department of Pharmacology, UTHSCSA
摘要：
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 Gq-coupled receptor on PI 3-kinase/Akt signaling and p70 6S kinase activation using Rat-1 fibroblasts stably expressing the human α1A adrenergic receptor. Treatment of the cells with phenylephrine, a specific α1 adrenergic receptor agonist, activated p70 S6 kinase but did not activated PI 3-kinase or any of the three known isoforms of Akt. Furthermore, phenylephrine blocked the 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 IRS-1, as the α1 adrenergic receptor agonist also inhibited the PDGF-induced activation of PI-3 kinase and Akt-1. Although increasing the intracellular Ca2+ 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 was reflected in a differential ability to protect cells from UV-induced apoptosis. These results demonstrated that activation of p70 S6 kinases by α1A adrenergic receptor in Rat-1 fibroblasts occurs in the absence of PI-3 kinase/Akt signaling. Furthermore, this receptor negatively regulates the PI 3-kinse/Akt pathway, resulting in enhanced cell death following apoptotic insult.