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J. Biol. Chem. 274 (2): 1131-1139

© 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

Phospholipase D and Its Product, Phosphatidic Acid, Mediate Agonist-dependent Raf-1 Translocation to the Plasma Membrane and the Activation of the Mitogen-activated Protein Kinase Pathway*

Mark A. Rizzo{ddagger}, Kuntala Shome{ddagger}, Chandrasekaran Vasudevan{ddagger}, Donna B. Stolz§, Tsung-Chang Sung||, Michael A. Frohman||, Simon C. Watkins§, , and Guillermo Romero{ddagger}**

From the {ddagger}Department of Pharmacology, §Department of Cell Biology and Physiology, the Center for Biological Imaging of the University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and from the ||Department of Pharmacological Sciences and the Institute for Cell and Developmental Biology, State University of New York, Stony Brook, New York 11794

ABSTRACT Back to Top

Abstract: The primary known function of phospholipase D (PLD) is to generate phosphatidic acid (PA) via the hydrolysis of phosphatidylcholine. However, the functional role of PA is not well understood. We report here evidence that links the activation of PLD by insulin and the subsequent generation of PA to the activation of the Raf-1-mitogen-activated protein kinase (MAPK) cascade. Brefeldin A (BFA), an inhibitor of the activation of ADP-ribosylation factor proteins, inhibited insulin-dependent production of PA and MAPK phosphorylation. The addition of PA reversed the inhibition of MAPK activation by BFA. Overexpression of a catalytically inactive variant of PLD2, but not PLD1, blocked insulin-dependent activation of PLD and phosphorylation of MAPK. Real time imaging analysis showed that insulin induced Raf-1 translocation to cell membranes by a process that was inhibited by BFA. PA addition reversed the effects of BFA on Raf-1 translocation. However, PA did not activate Raf-1 in vitro or in vivo, suggesting that the primary function of PA is to enhance the recruitment of Raf-1 to the plasma membrane where other factors may activate it. Finally, we found that the recruitment of Raf-1 to the plasma membrane was transient, but Raf-1 remained bound to endocytic vesicles.

Received for publication October 2, 1998.


* This work was supported by National Institutes of Health Grants DK51183, DK02465, 5-T32-GM08424-04, and GM54813 and American Diabetes Association Grant 96-029.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. Tel.: 412-648-9408; Fax: 412-648-1945; E-mail: ggr+{at}

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   Abstract »    Full Text »    PDF »
Elicitation of Suspension-Cultured Tomato Cells Triggers the Formation of Phosphatidic Acid and Diacylglycerol Pyrophosphate.
A. H. van der Luit, T. Piatti, A. van Doorn, A. Musgrave, G. Felix, T. Boller, and T. Munnik (2000)
Plant Physiology 123, 1507-1516
   Abstract »    Full Text »
Ras/Mitogen-Activated Protein Kinase Mediates Norepinephrine-Induced Phospholipase D Activation in Rabbit Aortic Smooth Muscle Cells by a Phosphorylation-Dependent Mechanism.
M. M. Muthalif, J.-H. Parmentier, I. F. Benter, N. Karzoun, A. Ahmed, Z. Khandekar, M. Z. Adl, S. Bourgoin, and K. U. Malik (2000)
J. Pharmacol. Exp. Ther. 293, 268-274
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A Role for Phospholipase D in GLUT4 Glucose Transporter Translocation.
M. Emoto, J. K. Klarlund, S. B. Waters, V. Hu, J. M. Buxton, A. Chawla, and M. P. Czech (2000)
J. Biol. Chem. 275, 7144-7151
   Abstract »    Full Text »    PDF »
Phospholipase D Stimulation by Receptor Tyrosine Kinases Mediated by Protein Kinase C and a Ras/Ral Signaling Cascade.
M. Voss, P. A. O. Weernink, S. Haupenthal, U. Moller, R. H. Cool, B. Bauer, J. H. Camonis, K. H. Jakobs, and M. Schmidt (1999)
J. Biol. Chem. 274, 34691-34698
   Abstract »    Full Text »    PDF »
Sequential Actions of Phospholipase D and Phosphatidic Acid Phosphohydrolase 2b Generate Diglyceride in Mammalian Cells.
V. A. Sciorra and A. J. Morris (1999)
Mol. Biol. Cell 10, 3863-3876
   Abstract »    Full Text »
Differential Phospholipase D Activation by Bradykinin and Sphingosine 1-Phosphate in NIH 3T3 Fibroblasts Overexpressing Gelsolin.
Y. Banno, H. Fujita, Y. Ono, S. Nakashima, Y. Ito, N. Kuzumaki, and Y. Nozawa (1999)
J. Biol. Chem. 274, 27385-27391
   Abstract »    Full Text »    PDF »
HSP27 in signal transduction and association with contractile proteins in smooth muscle cells.
A. I. Ibitayo, J. Sladick, S. Tuteja, O. Louis-Jacques, H. Yamada, G. Groblewski, M. Welsh, and K. N. Bitar (1999)
Am J Physiol Gastrointest Liver Physiol 277, G445-G454
   Abstract »    Full Text »    PDF »
A Role for Rho-kinase in Rho-controlled Phospholipase D Stimulation by the m3 Muscarinic Acetylcholine Receptor.
M. Schmidt, M. Voss, P. A. O. Weernink, J. Wetzel, M. Amano, K. Kaibuchi, and K. H. Jakobs (1999)
J. Biol. Chem. 274, 14648-14654
   Abstract »    Full Text »    PDF »
EGF-mediated caveolin recruitment to early endosomes and MAPK activation. Role of cholesterol and actin-cytoskeleton.
A. Pol, A. Lu, M. Pons, S. Peiro, and C. Enrich (2000)
J. Biol. Chem.
   Abstract »
The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras.
M. A Rizzo, K. Shome, S. C Watkins, and G. Romero (2000)
J. Biol. Chem.
   Abstract »
Inhibition of Phospholipase D by Amphiphysins.
C. Lee, S. R. Kim, J.-K. Chung, M. A. Frohman, M. W. Kilimann, and S. G. Rhee (2000)
J. Biol. Chem. 275, 18751-18758
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Cardiac Phospholipase D2 Localizes to Sarcolemmal Membranes and Is Inhibited by alpha -Actinin in an ADP-ribosylation Factor-reversible Manner.
J. B. Park, J. H. Kim, Y. Kim, S. H. Ha, J. H. Kim, J.-S. Yoo, G. Du, M. A. Frohman, P.-G. Suh, and S. H. Ryu (2000)
J. Biol. Chem. 275, 21295-21301
   Abstract »    Full Text »    PDF »
Evidence for the Involvement of Diacylglycerol Kinase in the Activation of Hypoxia-inducible Transcription Factor 1 by Low Oxygen Tension.
J. Aragones, D. R. Jones, S. Martin, M. A. S. Juan, A. Alfranca, F. Vidal, A. Vara, I. Merida, and M. O. Landazuri (2001)
J. Biol. Chem. 276, 10548-10555
   Abstract »    Full Text »    PDF »
The cAMP-specific phosphodiesterase PDE4D3 is regulated by phosphatidic acid binding consequences for cAMP signaling pathway, and characterization of a phosphatidic acid binding site.
M. Grange, C. Sette, M. Cuomo, M. Conti, M. Lagarde, A.-F. Prigent, and G. Nemoz (2000)
J. Biol. Chem.
   Abstract »
Actin Directly Interacts with Phospholipase D, Inhibiting Its Activity.
S. Lee, J. B. Park, J. H. Kim, Y. Kim, J. H. Kim, K.-J. Shin, J. S. Lee, S. H. Ha, P.-G. Suh, and S. H. Ryu (2001)
J. Biol. Chem. 276, 28252-28260
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Regulation of Constitutive Protein Transit by Phospholipase D in HT29-cl19A Cells.
L.-A. Denmat-Ouisse, C. Phebidias, P. Honkavaara, P. Robin, B. Geny, D. S. Min, S. Bourgoin, M. A. Frohman, and M.-N. Raymond (2001)
J. Biol. Chem. 276, 48840-48846
   Abstract »    Full Text »    PDF »
Involvement of Phospholipase D in Sphingosine 1-Phosphate-induced Activation of Phosphatidylinositol 3-Kinase and Akt in Chinese Hamster Ovary Cells Overexpressing EDG3.
Y. Banno, Y. Takuwa, Y. Akao, H. Okamoto, Y. Osawa, T. Naganawa, S. Nakashima, P.-G. Suh, and Y. Nozawa (2001)
J. Biol. Chem. 276, 35622-35628
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Agonist-dependent Traffic of Raft-associated Ras and Raf-1 Is Required for Activation of the Mitogen-activated Protein Kinase Cascade.
M. A. Rizzo, C. A. Kraft, S. C. Watkins, E. S. Levitan, and G. Romero (2001)
J. Biol. Chem. 276, 34928-34933
   Abstract »    Full Text »    PDF »

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