Am J Physiol Cell Physiol AJP citation statistics
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Cell Physiol (October 17, 2001). doi:10.1152/ajpcell.00260.2001
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
282/3/C545    most recent
00260.2001v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shvartsman, S. Y
Right arrow Articles by Lauffenburger, D. A
Right arrow Search for Related Content
PubMed
Right arrow Articles by Shvartsman, S. Y
Right arrow Articles by Lauffenburger, D. A

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

Context-dependent signaling in autocrine loops with positive feedback: modeling and experiments in the EGFR system

Stanislav Y Shvartsman1, Michael P Hagan2, A Yacoub2, Paul Dent3, Steven H Wiley4, and Douglas A Lauffenburger5*

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.




This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
T. Iwasa, I. Okamoto, M. Suzuki, E. Hatashita, Y. Yamada, M. Fukuoka, K. Ono, and K. Nakagawa
Inhibition of Insulin-Like Growth Factor 1 Receptor by CP-751,871 Radiosensitizes Non-Small Cell Lung Cancer Cells
Clin. Cancer Res., August 15, 2009; 15(16): 5117 - 5125.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
B. Schoeberl, E. A. Pace, J. B. Fitzgerald, B. D. Harms, L. Xu, L. Nie, B. Linggi, A. Kalra, V. Paragas, R. Bukhalid, et al.
Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor-PI3K Axis
Sci. Signal., June 30, 2009; 2(77): ra31 - ra31.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
O. Brandman, J. E. Ferrell Jr., R. Li, and T. Meyer
Interlinked Fast and Slow Positive Feedback Loops Drive Reliable Cell Decisions
Science, October 21, 2005; 310(5747): 496 - 498.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
E. K. Chu, J. S. Foley, J. Cheng, A. S. Patel, J. M. Drazen, and D. J. Tschumperlin
Bronchial Epithelial Compression Regulates Epidermal Growth Factor Receptor Family Ligand Expression in an Autocrine Manner
Am. J. Respir. Cell Mol. Biol., May 1, 2005; 32(5): 373 - 380.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. Hagan, A. Yacoub, and P. Dent
Ionizing Radiation Causes a Dose-Dependent Release of Transforming Growth Factor {alpha} In vitro from Irradiated Xenografts and during Palliative Treatment of Hormone-Refractory Prostate Carcinoma
Clin. Cancer Res., September 1, 2004; 10(17): 5724 - 5731.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Biol.Home page
B. N Kholodenko
Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors
J. Exp. Biol., June 15, 2003; 206(12): 2073 - 2082.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 1976 by the American Physiological Society.