title: Multiple cellular proteins modulate the dynamics of K-ras association with the plasma membrane.
abstract: Although specific proteins have been identified that regulate the membrane association and facilitate intracellular transport of prenylated Rho- and Rab-family proteins, it is not known whether cellular proteins fulfill similar roles for other prenylated species, such as Ras-family proteins. We used a previously described method to evaluate how several cellular proteins, previously identified as potential binding partners (but not effectors) of K-ras4B, influence the dynamics of K-ras association with the plasma membrane. Overexpression of either PDEδ or PRA1 enhances, whereas knockdown of either protein reduces, the rate of dissociation of K-ras from the plasma membrane. Inhibition of calmodulin likewise reduces the rate of K-ras dissociation from the plasma membrane, in this case in a manner specific for the activated form of K-ras. By contrast, galectin-3 specifically reduces the rate of plasma membrane dissociation of activated K-ras, an effect that is blocked by the K-ras antagonist farnesylthiosalicylic acid (salirasib). Multiple cellular proteins thus control the dynamics of membrane association and intercompartmental movement of K-ras to an important degree even under basal cellular conditions.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors.forename: Pinkesh
authors.initials: P
authors.lastname: Bhagatji
authors.forename: Rania
authors.initials: R
authors.lastname: Leventis
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rich
authors.forename: Chen-ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: John R
authors.initials: JR
authors.lastname: Silvius
mesh_terms: D000595:Amino Acid Sequence; D002147:Calmodulin / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D054876:Prenylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D002147:Calmodulin; D037502:Galectin 3; C117307:KRAS protein, human; D010455:Peptides; D012459:Salicylates; D033921:Vesicular Transport Proteins; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D019204:GTP-Binding Proteins; C108941:RABAC1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus