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Compartment-Specific Feedback Loop and Regulated Trafficking Can Result in Sustained Activation of Ras at the Golgi

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029

Correspondence: Address reprint requests to Ravi Iyengar, Dept. of Pharmacology and Biological Chemistry, Box 1215 Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029. Tel.: 212-659-1707; Fax: 212-831-0114; E-mail: ravi.iyengar{at}mssm.edu.

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- (PLC-) driven feedback loop, can convert a transient calcium signal into prolonged Ras activation at the Golgi. Detailed analysis of the network identified PLC- as a key determinant of "compartment switching". Modulation of PLC- 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.