Am J Physiol Cell Physiol AJP: Advances in Physiology Education
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Cell Physiol 282: C545-C559, 2002. First published October 17, 2001; doi:10.1152/ajpcell.00260.2001
0363-6143/02 $5.00
This Article
Right arrow Full Text
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
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
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 Web of Science (53)
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 PubMed Citation
Right arrow Articles by Shvartsman, S. Y.
Right arrow Articles by Lauffenburger, D. A.
Vol. 282, Issue 3, C545-C559, March 2002

Autocrine loops with positive feedback enable context-dependent cell signaling

S. Y. Shvartsman1, M. P. Hagan2, A. Yacoub2, P. Dent2, H. S. Wiley3, and D. A. Lauffenburger4

1 Department of Chemical Engineering and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544; 2 Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia 23298-0058; 3 Fundamental Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352; and 4 Division of Bioengineering and Environmental Health, Department of Chemical Engineering, and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

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, amplitude and duration of mitogen-activated protein kinase (MAPK) 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 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 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 transient or sustained, depending on cell type and composition of the extracellular medium. On the basis of 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.

mathematical model; epidermal growth factor receptor; ligand shedding; ionizing radiation; mitogen-activated protein kinase; cross-activation


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 TABLE OF CONTENTS
Visit Other APS Journals Online