Understanding the Living Cell in the 21st Century: Mathematics at Last

Boris Kholodenko
Thomas Jefferson University

Extracellular information received by plasma membrane receptors is processed and encoded into complex temporal and spatial patterns of phosphorylation and topological relocation of signaling proteins. We quantify cell signaling in terms of the sensitivity of a target (a transcription factor) to a signal (a hormone). Our experimental monitoring and computational modeling of growth factor signaling revealed kinetic and molecular factors that control the time course of phosphorylation responses, such as transient versus sustained activation patterns and oscillations in protein phosphorylation state. Modeling of a 4D-organization of protein phosphorylation (MAPK) cascades demonstrates that the spatial separation of kinases and phosphatases may cause precipitous spatial gradients of activated kinases (MEK and ERK) resulting in a strong attenuation of the signal towards the nucleus. The results suggest that there are additional (besides simple diffusion) molecular mechanisms that facilitate passing of signals from the plasma membrane to transcription factors in the nucleus. They may involve phospho-protein trafficking within endocytic vesicles and active transport of signaling complexes by molecular motors.

Created: 5/6/02 DAR
Edited: 5/6/02