title: Regulation of phospholipase D activity by actin. Actin exerts bidirectional modulation of Mammalian phospholipase D activity in a polymerization-dependent, isoform-specific manner.
abstract: Many critical cellular processes, including proliferation, vesicle trafficking, and secretion, are regulated by both phospholipase D (PLD) and the actin microfilament system. Stimulation of human PLD1 results in its association with the detergent-insoluble actin cytoskeleton, but the molecular mechanisms and functional consequences of PLD-actin interactions remain incompletely defined. Biochemical and pharmacologic modulation of actin polymerization resulted in complex bidirectional effects on PLD activity, both in vitro and in vivo. Highly purified G-actin inhibited basal and stimulated PLD activity, whereas F-actin produced the opposite effects. Actin-induced modulation of PLD activity was independent of the activating stimulus. The efficacy and potency of the effects of actin were isoform-specific but broadly conserved among actin family members. Human betagamma-actin was only 45% as potent and 40% as efficacious as rabbit skeletal muscle alpha-actin, whereas its inhibitory profile was similar to the single actin species from the yeast, Saccharomyces cerevisiae. Use of actin polymerization-specific reagents indicated that PLD1 binds both monomeric G-actin, as well as actin filaments. These data are consistent with a model in which the physical state of the actin cytoskeleton is a critical determinant of its regulation of PLD activity.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Inflammation Program, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242, USA. david-kusner@uiowa.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Kusner
authors.forename: James A
authors.initials: JA
authors.lastname: Barton
authors.forename: Kuo-Kuang
authors.initials: KK
authors.lastname: Wen
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rubenstein
authors.forename: Shankar S
authors.initials: SS
authors.lastname: Iyer
mesh_terms: D000199:Actins / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D003850:Deoxyribonuclease I / Q000494:pharmacology; D047630:Depsipeptides; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D015636:Magnesium Chloride / Q000494:pharmacology; D008322:Mammals; D008387:Marine Toxins / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010590:Phalloidine / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism*; D020033:Protein Isoforms / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D020298:U937 Cells
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D046911:Macromolecular Substances; D008387:Marine Toxins; D010456:Peptides, Cyclic; D020033:Protein Isoforms; D013844:Thiazoles; D053778:Thiazolidines; D015636:Magnesium Chloride; C057531:jasplakinolide; D010590:Phalloidine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003850:Deoxyribonuclease I; D010739:Phospholipase D; C037068:latrunculin B; D013755:Tetradecanoylphorbol Acetate