PHYSICAL MODULATION OF INTRACELLULAR SIGNALING PROCESSES BY LOCATIONAL REGULATION

Recent observations in the field of signal transduction suggest that w here a protein is located within a cell can be as important as its act ivity measured in solution for activation of its downstream pathway, T he physical organization of the cell can provide an additional layer o f control upon the chemical reaction networks that govern ultimately p erceived signals. Using the cytosol and plasma membrane as relevant co mpartmental distinctions, we analyze the effect of relocation on the r ate of association with a membrane-associated target. We quantify this effect as an enhancement factor E in terms of measurable parameters s uch as the number of available targets, molecular diffusivities, and i ntrinsic reaction rate constants. We then employ two simple yet releva nt example models to illustrate how relocation can affect the dynamics of signal transduction pathways. The temporal profiles and phase beha vior of these models are investigated. We also relate experimentally o bservable aspects of signal transduction such as peak activation and t he relative time scales of stimulus and response to quantitative aspec ts of the relocation mechanisms in our models. In our example schemes, nearly complete relocation of the cytosolic species in the signaling pair is required to generate meaningful activation of the model pathwa ys when the association rate enhancement factor E is as low as 10; whe n E is 100 or greater, only a small fraction of the protein must be re located.