title: Compartment-specific feedback loop and regulated trafficking can result in sustained activation of Ras at the Golgi.
abstract: Imaging experiments have shown that cell signaling components such as Ras can be activated by growth factors at distinct subcellular locations. Trafficking between these subcellular locations is a regulated dynamic process. The effects of trafficking and the molecular mechanisms underlying compartment-specific Ras activation were studied using numerical simulations of an ordinary differential equation-based multi-compartment model. The simulations show that interplay between two distinct mechanisms, a palmitoylation cycle that controls Ras trafficking and a phospholipase C-epsilon (PLC-epsilon) driven feedback loop, can convert a transient calcium signal into prolonged Ras activation at the Golgi. Detailed analysis of the network identified PLC-epsilon as a key determinant of "compartment switching". Modulation of PLC-epsilon activity switches the location of activated Ras between the plasma membrane and Golgi through a new mechanism termed "kinetic scaffolding". These simulations indicate that multiple biochemical mechanisms, when appropriately coupled, can give rise to an intracellular compartment-specific sustained Ras activation in response to stimulation of growth factor receptors at the plasma membrane.
authors.affiliation: Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Narat J
authors.initials: NJ
authors.lastname: Eungdamrong
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
mesh_terms: D020013:Calcium Signaling / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D005246:Feedback / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism*; D008954:Models, Biological; D054801:Phosphoinositide Phospholipase C; D021381:Protein Transport / Q000502:physiology; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017978:Receptors, Growth Factor; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D018631:ras Proteins