Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses
Abstract Deregulation of ErbB signaling plays a key role in the progression of multiple human cancers. To help understand ErbB signaling quantitatively, in this work we combine traditional experiments with computational modeling, building a model that describes how stimulation of all four ErbB recep...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2007-11-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/msb4100188 |
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| _version_ | 1849225762228404224 |
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| author | Marc R Birtwistle Mariko Hatakeyama Noriko Yumoto Babatunde A Ogunnaike Jan B Hoek Boris N Kholodenko |
| author_facet | Marc R Birtwistle Mariko Hatakeyama Noriko Yumoto Babatunde A Ogunnaike Jan B Hoek Boris N Kholodenko |
| author_sort | Marc R Birtwistle |
| collection | DOAJ |
| description | Abstract Deregulation of ErbB signaling plays a key role in the progression of multiple human cancers. To help understand ErbB signaling quantitatively, in this work we combine traditional experiments with computational modeling, building a model that describes how stimulation of all four ErbB receptors with epidermal growth factor (EGF) and heregulin (HRG) leads to activation of two critical downstream proteins, extracellular‐signal‐regulated kinase (ERK) and Akt. Model analysis and experimental validation show that (i) ErbB2 overexpression, which occurs in approximately 25% of all breast cancers, transforms transient EGF‐induced signaling into sustained signaling, (ii) HRG‐induced ERK activity is much more robust to the ERK cascade inhibitor U0126 than EGF‐induced ERK activity, and (iii) phosphoinositol‐3 kinase is a major regulator of post‐peak but not pre‐peak EGF‐induced ERK activity. Sensitivity analysis leads to the hypothesis that ERK activation is robust to parameter perturbation at high ligand doses, while Akt activation is not. |
| format | Article |
| id | doaj-art-5308beffef2345ef98a807eb6d85b538 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2007-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-5308beffef2345ef98a807eb6d85b5382025-08-24T12:02:06ZengSpringer NatureMolecular Systems Biology1744-42922007-11-013111610.1038/msb4100188Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analysesMarc R Birtwistle0Mariko Hatakeyama1Noriko Yumoto2Babatunde A Ogunnaike3Jan B Hoek4Boris N Kholodenko5Department of Chemical Engineering, University of DelawareComputational and Experimental Systems Biology Group, RIKEN Genomic Sciences CenterComputational and Experimental Systems Biology Group, RIKEN Genomic Sciences CenterDepartment of Chemical Engineering, University of DelawareDepartment of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityDepartment of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityAbstract Deregulation of ErbB signaling plays a key role in the progression of multiple human cancers. To help understand ErbB signaling quantitatively, in this work we combine traditional experiments with computational modeling, building a model that describes how stimulation of all four ErbB receptors with epidermal growth factor (EGF) and heregulin (HRG) leads to activation of two critical downstream proteins, extracellular‐signal‐regulated kinase (ERK) and Akt. Model analysis and experimental validation show that (i) ErbB2 overexpression, which occurs in approximately 25% of all breast cancers, transforms transient EGF‐induced signaling into sustained signaling, (ii) HRG‐induced ERK activity is much more robust to the ERK cascade inhibitor U0126 than EGF‐induced ERK activity, and (iii) phosphoinositol‐3 kinase is a major regulator of post‐peak but not pre‐peak EGF‐induced ERK activity. Sensitivity analysis leads to the hypothesis that ERK activation is robust to parameter perturbation at high ligand doses, while Akt activation is not.https://doi.org/10.1038/msb4100188breast cancerkinetic analysismathematical modelingreceptor tyrosine kinases |
| spellingShingle | Marc R Birtwistle Mariko Hatakeyama Noriko Yumoto Babatunde A Ogunnaike Jan B Hoek Boris N Kholodenko Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses Molecular Systems Biology breast cancer kinetic analysis mathematical modeling receptor tyrosine kinases |
| title | Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses |
| title_full | Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses |
| title_fullStr | Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses |
| title_full_unstemmed | Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses |
| title_short | Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses |
| title_sort | ligand dependent responses of the erbb signaling network experimental and modeling analyses |
| topic | breast cancer kinetic analysis mathematical modeling receptor tyrosine kinases |
| url | https://doi.org/10.1038/msb4100188 |
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