Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid.
Mitogens activate protein translation through phosphorylation of p7S6 kinase (p70(S6K)) 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 p70(S6K) 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, p70(S6K), 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
Yoonseok
Y
Howard Hughes Medical Institute and the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Exton
John H
JH
D020001:1-Butanol / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D005347:Fibroblasts; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids / Q000494:pharmacology*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D020001:1-Butanol; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D019869:Phosphatidylinositol 3-Kinases; D010739:Phospholipase D; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D013755:Tetradecanoylphorbol Acetate; C499526:Eif4ebp1 protein, rat; C031815:toxB protein, Clostridium difficile; C546845:mTOR protein, rat; C494920:Akt1 protein, rat; C105606:phospholipase D2; C106801:phospholipase D1