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Howard Hughes Medical Institute and the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
1Correspondence. Howard Hughes Medical Institute and the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. E-mail: john.exton{at}vanderbilt.edu
Mitogens activate protein translation through phosphorylation of p7S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1) mediated by the mammalian target of rapamycin (mTOR) or phosphoinositide 3-kinase (PI3K). A recent report (Science 294, 1942, 2001) has implicated phospholipase D (PLD) in mTOR signaling. We studied the role of PLD in the phosphorylation of p70S6K and 4E-BP1 induced by lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) using fibroblasts deficient in PLD activity and also 1-butanol, which inhibits phosphatidic acid production by PLD. The reduction in PLD activity in both situations impaired the effect of LPA on mTOR signaling but did not inhibit the effect of PDGF. PDGF induced marked phosphorylation of Akt (a PI3K target) but this was not affected by PLD deficiency. LPA caused much less phosphorylation of Akt and this was dependent on PLD activity. Toxin B, which inactivates Rho GTPases, markedly impaired PLD1 activation and phosphorylation of Akt, p70S6K, and 4E-BP1 induced by LPA but had a minimal or no effect on the actions of PDGF. These results support the hypothesis that LPA activates protein translation through the action of PLD1-generated PA on mTOR and the PI3K/Akt pathway whereas PDGF acts through P13K/Akt independent of PLD1.—Kam, Y., Exton, J. H. Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid.
Key Words: platelet-derived growth factor • phosphoinositide 3-kinase
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