Spatial range of autocrine signaling: modeling and computational analysis

Abstract

Autocrine loops formed by growth factors and their receptors have been identified in a large number of developmental, physiological, and pathological contexts. In general, the spatially distributed and recursive nature of autocrine signaling systems makes their experimental analysis, and often even their detection, very difficult. Here, we combine Brownian motion theory, Monte Carlo simulations, and reaction-diffusion models to analyze the spatial operation of autocrine loops. Within this modeling framework, the ability of autocrine cells to recapture the endogenous ligand and the distances traveled by autocrine ligands are explicitly related to ligand diffusion coefficients, density of surface receptors, ligand secretion rate, and rate constants of ligand binding and endocytic internalization. Applying our models to study autocrine loops in the epidermal growth factor receptor system, we find that autocrine loops can be highly localized--even at the level of a single cell. We demonstrate how the variations in molecular and cellular parameters may "tune" the spatial range of autocrine signals over several orders of magnitude: from microns to millimeters. We argue that this versatile regulation of the spatial range of autocrine signaling enables autocrine cells to perceive a broad spectrum of environmental information.