Structure of the EGF receptor transactivation circuit integrates with cell context
Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of t...
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| Format: | Article |
| Language: | en_US |
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Royal Society of Chemistry
2012
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| Online Access: | http://hdl.handle.net/1721.1/68646 |
| _version_ | 1826195031738810368 |
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| author | Joslin, Elizabeth J. Shankaran, Harish Opresko, Lee K. Bollinger, Nikki Lauffenburger, Douglas A. Wiley, H. Steven |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Joslin, Elizabeth J. Shankaran, Harish Opresko, Lee K. Bollinger, Nikki Lauffenburger, Douglas A. Wiley, H. Steven |
| author_sort | Joslin, Elizabeth J. |
| collection | MIT |
| description | Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a “non-binding” reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway. |
| first_indexed | 2024-09-23T10:06:06Z |
| format | Article |
| id | mit-1721.1/68646 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:06:06Z |
| publishDate | 2012 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | mit-1721.1/686462022-09-26T15:41:10Z Structure of the EGF receptor transactivation circuit integrates with cell context Joslin, Elizabeth J. Shankaran, Harish Opresko, Lee K. Bollinger, Nikki Lauffenburger, Douglas A. Wiley, H. Steven Massachusetts Institute of Technology. Department of Biological Engineering Lauffenburger, Douglas A. Lauffenburger, Douglas A. Joslin, Elizabeth J. Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a “non-binding” reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway. Pacific Northwest National Laboratory (U.S.) (Biomolecular Systems Initiative LDRD Program) National Institutes of Health (U.S.) (NIH grant CA96504) Whitaker Foundation 2012-01-23T22:08:23Z 2012-01-23T22:08:23Z 2010-05 2010-03 Article http://purl.org/eprint/type/JournalArticle 1742-206X 1742-2051 http://hdl.handle.net/1721.1/68646 Joslin, Elizabeth J. et al. “Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context.” Molecular BioSystems 6.7 (2010): 1293.© 2010 Royal Society of Chemistry. en_US http://dx.doi.org/10.1039/C003921G Molecular BioSystems Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Royal Society of Chemistry Prof. Lauffenburger |
| spellingShingle | Joslin, Elizabeth J. Shankaran, Harish Opresko, Lee K. Bollinger, Nikki Lauffenburger, Douglas A. Wiley, H. Steven Structure of the EGF receptor transactivation circuit integrates with cell context |
| title | Structure of the EGF receptor transactivation circuit integrates with cell context |
| title_full | Structure of the EGF receptor transactivation circuit integrates with cell context |
| title_fullStr | Structure of the EGF receptor transactivation circuit integrates with cell context |
| title_full_unstemmed | Structure of the EGF receptor transactivation circuit integrates with cell context |
| title_short | Structure of the EGF receptor transactivation circuit integrates with cell context |
| title_sort | structure of the egf receptor transactivation circuit integrates with cell context |
| url | http://hdl.handle.net/1721.1/68646 |
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