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First published on April 25, 2006; DOI: 10.1124/mol.105.021451

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Received for publication December 5, 2005.
Revised April 18, 2006.
Accepted for publication April 25, 2006.

Direct modulation of phospholipase D activity by G{beta}{gamma}

Anita M Preininger 1, Lee G Henage 1, William M Oldham 1, Eun Ja Yoon 1, Heidi E Hamm 1, H. Alex Brown 1*

1 Vanderbilt University Medical Center

* Address correspondence to: E-mail: alex.brown{at}vanderbilt.edu

Abstract

Abstract: Phospholipase D-mediated hydrolysis of phosphatidylcholine is stimulated by PKC 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{beta}{gamma} subunits of heterotrimeric G-proteins. GPCR activation alters affinity between G{alpha} and G{beta}{gamma} subunits, allowing subsequent interaction with distinct effectors. G{beta}1{gamma}1 inhibited phospholipase D1 and phospholipase D2 activity, and both G{beta}1{gamma}1 and G{beta}1{gamma}2 inhibited stimulated phospholipase D1 activity in a dose-dependent manner in reconstitution assays. Reconstitution assays suggest this interaction occurs through the amino terminus of phospholipase D, as G{beta}1{gamma}1 is unable to inhibit an amino-terminally truncated phospholipase D construct, PLD1.d311, which like full-length phospholipase D isoforms, requires PIP2 for activity. Furthermore, a truncated protein consisting of the amino terminal region of phospholipase D containing the PX/PH domains was found to interact with G{beta}1{gamma}1, unlike the PLD1.d311 recombinant protein which lacks this domain. In vivo, expressed recombinant G{beta}1{gamma}2 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{beta}{gamma} directly regulates phospholipase D activity in vitro, and suggest a novel mechanism to negatively regulate phospholipase D signaling in vivo.


Key words: Phospholipase D's, Protein Kinase C, Cdc42, rho, rac, other small G proteins


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