Computational modeling of the EGF-receptor system: a paradigm for systems biology

doi:10.1016/S0962-8924(02)00009-0

Trends in Cell Biology

Volume 13, Issue 1, January 2003, Pages 43-50

https://doi.org/10.1016/S0962-8924(02)00009-0 Get rights and content

Abstract

Computational models have rarely been used as tools by biologists but, when models provide experimentally testable predictions, they can be extremely useful. The epidermal growth factor receptor (EGFR) is probably the best-understood receptor system, and computational models have played a significant part in its elucidation. For many years, models have been used to analyze EGFR dynamics and to interpret mutational studies, and are now being used to understand processes including signal transduction, autocrine loops and developmental patterning. The success of EGFR modeling can be a guide to combining models and experiments productively to understand complex biological processes as integrated systems.

Section snippets

Binding and trafficking

The original models of EGFR binding and internalization were derived from classic enzyme kinetics 5, 6, 7. Receptor-mediated endocytosis was modeled as an enzymatic process in which surface-associated EGF was considered to be a ‘substrate’, internalized EGF was the ‘product’ and coated pits were the ‘enzyme’. This modeling approach was experimentally accessible because of the availability of radiolabeled EGF and the discovery that a simple acidic cell wash could selectively release

Signaling and functional responses

Considerable insights have been gained from combining quantitative experimental and modeling approaches to EGFR trafficking problems. An important benefit of quantitatively understanding EGFR trafficking dynamics is the improved ability to interpret data on cells' functional responses and the signal transduction processes governing them. As one simple example, the relationship between external concentrations of EGF and cell proliferation appears to be complex (as characterized by measures such

Interactions between EGFR-family members

The EGFR can form homodimers with itself and heterodimers with other members of its receptor-family, such as ErbB-2 [40]. Forming multimers can significantly affect receptor behavior such as ligand affinity and these processes have been extensively modeled. Interestingly, modeling of receptor dimerization demonstrated almost a decade ago that the multiple affinity forms of this receptor could not be explained by occupancy-induced dimerization [41]. Instead, the models suggested that either

Autocrine signaling

The EGFR itself is only a single part of the overall EGFR system. Within an organism, receptors are part of a system that includes the cognate ligand and all of the regulatory components controlling upstream aspects of ligand availability and downstream signal transduction. Although models have been useful for understanding EGFR dynamics, they are also proving to be essential for understanding the overall operation of the EGFR system. Autocrine signaling is an excellent example of how a

Transactivation and positive feedback

One of the most interesting aspects of autocrine EGFR signaling is that ligand processing and release are regulated by extracellular signals. In particular, Ras–MAPK signaling and intracellular calcium levels are major regulators of EGFR ligand release 55, 56. This appears to be the main mechanism responsible for EGFR ‘transactivation’ by other hormones (Fig. 3b). However, these signaling pathways are also activated by the EGFR itself. Combined with the high probability of autocrine-ligand

Future directions: integrated models

We have described here many of the models of the EGFR system that have been built and experimentally validated during the past 20 years. Some of these models have been used to analyze the system and to predict new and unexpected properties. So, what have we learned and how should this guide our future efforts in systems biology? First, we have learned that models are only useful if experiments can be designed that directly test specific predictions of the model; in other words, the predictions

Concluding remarks

The EGFR system appears to behave as a proportional control system in which signal processing occurs at many different points in the pathway. It is clear that cells ‘filter’ the information that they receive before passing it to the nucleus. The many different control points in the EGFR pathway make it an excellent system for investigating how cells process contextual information. We expect that computational models will be essential for understanding this process. Fortunately, the days of

Acknowledgements

Our work has been supported over the years by the National Institutes of Health, the National Science Foundation, the US Department of Defense and the US Department of Energy.

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Trends in Cell Biology

Computational modeling of the EGF-receptor system: a paradigm for systems biology

Abstract

Section snippets

Binding and trafficking

Signaling and functional responses

Interactions between EGFR-family members

Autocrine signaling

Transactivation and positive feedback

Future directions: integrated models

Concluding remarks

Acknowledgements

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Dev. Biol.

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J. Biol. Chem.

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J. Theor. Biol.

The EGF receptor: a nexus for trafficking and signaling

BioEssays