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Biophys J, October 2001, p. 1854-1867, Vol. 81, No. 4
and
*Department of Chemical Engineering, Division of
Bioengineering and Environmental Health, Center for
Cancer Research, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, and §Environmental and Health
Sciences Division, Pacific Northwest National Laboratory, Richland,
Washington 99352 USA
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.
Biophys J, October 2001, p. 1854-1867, Vol. 81, No. 4
© 2001 by the Biophysical Society 0006-3495/01/10/1854/14 $2.00
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