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Direct Modulation of Phospholipase D Activity by G

Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee

Phospholipase D-mediated hydrolysis of phosphatidylcholine is stimulated by protein kinase C and the monomeric G proteins Arf, RhoA, Cdc42, and Rac1, resulting in complex regulation of this enzyme. Using purified proteins, we have identified a novel inhibitor of phospholipase D activity, G subunits of heterotrimeric G proteins. G protein-coupled receptor activation alters affinity between G and G subunits, allowing subsequent interaction with distinct effectors. G₁₁ inhibited phospholipase D1 and phospholipase D2 activity, and both G₁₁ and G₁₂ inhibited stimulated phospholipase D1 activity in a dosedependent manner in reconstitution assays. Reconstitution assays suggest this interaction occurs through the amino terminus of phospholipase D, because G₁₁ is unable to inhibit an amino-terminally truncated phospholipase D construct, PLD1.d311, which like full-length phospholipase D isoforms, requires phosphatidylinositol-4,5-bisphosphate for activity. Furthermore, a truncated protein consisting of the amino-terminal region of phospholipase D containing the phox/pleckstrin homology domains was found to interact with G₁₁, unlike the PLD1.d311 recombinant protein, which lacks this domain. In vivo, expressed recombinant G₁₂ was also found to inhibit phospholipase D activity under basal and stimulated conditions in MDA-MB-231 cells, which natively express both phospholipase D1 and phospholipase D2. These data demonstrate that G directly regulates phospholipase D activity in vitro and suggest a novel mechanism to negatively regulate phospholipase D signaling in vivo.

Address correspondence to: Dr. H. Alex Brown, Department of Pharmacology: 442 RRB, Vanderbilt University School of Medicine, 23rd Ave. South and Pierce, Nashville, TN 37232-6600. E-mail: alex.brown{at}vanderbilt.edu

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