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Articles in PresS, published online ahead of print October 16, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00260.2001
Submitted on June 11, 2001
Accepted on October 15, 2001
1 Chemical Engineering and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
2 Radiation Oncology, Virginia Commonwealth Univresity, Richmond, VA, USA
3 Radiation Oncology, Virginia Commonwealth Univresity, Richmond, VA, USA; Radiation Oncology, Virginia Commonwealth Univresity, Richmond, VA, USA
4 Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, MA, USA
5 Fundamental Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
* To whom correspondence should be addressed. E-mail: stas{at}princeton.edu.
We describe a mechanism for context-dependent cell signaling mediated by autocrine loops with positive feedback. We demonstrate that the composition of the extracellular medium can critically influence the intracellular signaling dynamics induced by extracellular stimuli. Specifically, in the Epidermal Growth Factor Receptor (EGFR) system, both the amplitude and the duration of MAP Kinase activation are modulated by the positive feedback loop formed by the EGFR, the Ras-MAPK signaling pathway, and a ligand-releasing protease. The signaling response to a transient input is short-lived when most of the released ligand is lost to the cellular microenvironment by diffusion and/or interaction with an extracellular ligand-binding component. In contrast, the response is prolonged or persistent in a cell that is efficient in recapturing the endogenous ligand. To study the functional capabilities of autocrine loops, we have developed a mathematical model that accounts for ligand release, transport, binding, and intracellular signaling. We find that context-dependent signaling arises as a result of dynamic interaction between the parts of an autocrine loop. Using the model, we can directly interpret experimental observations on the context-dependent responses of autocrine cells to ionizing radiation. In human carcinoma cells, MAPK signaling patterns induced by a short pulse of ionizing radiation can be either transient or sustained, depending on the cell type and the composition the extracellular medium. Based on our model, we propose that autocrine loops in this, and potentially other growth factor and cytokine systems, may serve as modules for context-dependent cell signaling.
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