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

¹ Mount Sinai School of Medicine

^* To whom correspondence should be addressed. E-mail: ravi.iyengar{at}mssm.edu.

Submitted on July 11, 2006
Revised on August 10, 2006
Accepted on 11 October 2006

	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 a ODE based multi-compartment model. The simulations show that interplay between two distinct mechanisms, a palmitoylation cycle that controls Ras trafficking between the plasma membrane and Golgi and a phospholipase C-epsilon (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- 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.

Key Words: Compartmental Model, Palmitoylation, Phospholipase C, Ras activation, Signaling Network