title: Using inhibitors of prenylation to block localization and transforming activity.
abstract: The proper subcellular localization and biological activity of most Ras and Rho family small GTPases are dependent on their posttranslational modification by isoprenylation. Farnesyltransferase (FTase) and geranylgeranyl transferase I (GGTase I) are the prenyltransferases that catalyze the irreversible attachment of C15 farnesyl (Ras, Rnd) or C20 (R-Ras, Ral, Rap, Rho, Rac, Cdc42) isoprenoid lipid moieties to these small GTPases and other proteins. Therefore, pharmacological inhibitors of FTase (FTIs) and GGTase I (GGTIs) have been developed to prevent these modifications and thereby to block the lipid-mediated association of Ras and Rho proteins with cellular membranes and the consequent signaling and transforming activities. In addition, other small molecule inhibitors such as farnesyl thiosalicylic acid (FTS) can compete with the isoprenoid moiety of small GTPases for membrane binding sites. Finally, endogenous regulatory proteins such as RhoGDIs can bind to and mask the prenyl groups of small GTPases, leading to their sequestration from membranes. We describe here methods to use each of these categories of prenylation inhibitors to manipulate and investigate the subcellular localization patterns and transforming potential of these Ras and Rho family GTPases.
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Anastacia C
authors.initials: AC
authors.lastname: Berzat
authors.forename: Donita C
authors.initials: DC
authors.lastname: Brady
authors.forename: James J
authors.initials: JJ
authors.lastname: Fiordalisi
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D054876:Prenylation / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D012459:Salicylates / Q000494:pharmacology; D018631:ras Proteins / Q000037:antagonists & inhibitors; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D020730:Guanine Nucleotide Dissociation Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D005204:Farnesol; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase; D020558:GTP Phosphohydrolases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins