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Self-Organization of Polarized Cell Signaling via Autocrine Circuits: Computational Model Analysis

Ivan V. Maly ^*, H. Steven Wiley  and Douglas A. Lauffenburger ^*

^* Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352

Correspondence: Address reprint requests to Ivan V. Maly, Rm. 56-379, MIT, Cambridge, MA 02139. Tel.: 617-258-0208; Fax: 617-258-0248; E-mail: maly{at}mit.edu.

Recent studies have suggested that autocrine signaling through epidermal growth factor receptor (EGFR) might be involved in generating or maintaining an intrinsic polarity in tissue cells, possibly via spatial localization of EGFR-mediated signaling. The difficulty of experimental investigation of autocrine signaling makes especially valuable an application of computational modeling for critical hypotheses about the dynamic operation of the underlying signaling circuits, both intracellular and extracellular. Toward this end, we develop and analyze here a spatially distributed dynamic computational model of autocrine EGFR signaling. Under certain conditions, the model spontaneously evolves into a state wherein sustained signaling is spatially localized on smaller than cell dimension, conferring a polarity to the otherwise nonpolar model cell. Conditions of a sufficiently large rate of autocrine EGFR ligand release and of a sufficiently small exogenous ligand concentration are qualitatively consistent with experimental observations of EGFR-mediated migration. Thus, computational analysis supports the concept that autocrine EGFR signaling circuits could play a role in helping generate and/or maintain an intrinsic cell spatial polarity, possibly related to migration as well as tissue organization. We additionally offer particular suggestions for critical nodes in the EGFR signaling circuits governing this self-organization capability.

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