Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling
Abstract Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. I...
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| Format: | Article |
| Language: | English |
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Springer Nature
2009-04-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/msb.2009.19 |
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| _version_ | 1849225787547320320 |
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| author | Nikolay Borisov Edita Aksamitiene Anatoly Kiyatkin Stefan Legewie Jan Berkhout Thomas Maiwald Nikolai P Kaimachnikov Jens Timmer Jan B Hoek Boris N Kholodenko |
| author_facet | Nikolay Borisov Edita Aksamitiene Anatoly Kiyatkin Stefan Legewie Jan Berkhout Thomas Maiwald Nikolai P Kaimachnikov Jens Timmer Jan B Hoek Boris N Kholodenko |
| author_sort | Nikolay Borisov |
| collection | DOAJ |
| description | Abstract Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal‐regulated kinase) cascade, yet it enhances ERK activation by low EGF doses. We find that major crosstalk mechanisms that amplify ERK signaling are localized upstream of Ras and at the Ras/Raf level. Computational modeling unveils how critical network nodes, the adaptor proteins GAB1 and insulin receptor substrate (IRS), Src kinase, and phosphatase SHP2, convert insulin‐induced increase in the phosphatidylinositol‐3,4,5‐triphosphate (PIP3) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin‐induced amplification of mitogenic signaling is abolished by disrupting PIP3‐mediated positive feedback via GAB1 and IRS. We demonstrate that GAB1 behaves as a non‐linear amplifier of mitogenic responses and insulin endows EGF signaling with robustness to GAB1 suppression. Our results show the feasibility of using computational models to identify key target combinations and predict complex cellular responses to a mixture of external cues. |
| format | Article |
| id | doaj-art-b3f9700f51084c9f8a035694fd4de41c |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2009-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-b3f9700f51084c9f8a035694fd4de41c2025-08-24T11:58:49ZengSpringer NatureMolecular Systems Biology1744-42922009-04-015111510.1038/msb.2009.19Systems‐level interactions between insulin–EGF networks amplify mitogenic signalingNikolay Borisov0Edita Aksamitiene1Anatoly Kiyatkin2Stefan Legewie3Jan Berkhout4Thomas Maiwald5Nikolai P Kaimachnikov6Jens Timmer7Jan B Hoek8Boris N Kholodenko9Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityInstitute for Theoretical Biology, Humboldt UniversityDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityFreiburg Institute for Advanced Science, University of FreiburgDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityAbstract Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal‐regulated kinase) cascade, yet it enhances ERK activation by low EGF doses. We find that major crosstalk mechanisms that amplify ERK signaling are localized upstream of Ras and at the Ras/Raf level. Computational modeling unveils how critical network nodes, the adaptor proteins GAB1 and insulin receptor substrate (IRS), Src kinase, and phosphatase SHP2, convert insulin‐induced increase in the phosphatidylinositol‐3,4,5‐triphosphate (PIP3) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin‐induced amplification of mitogenic signaling is abolished by disrupting PIP3‐mediated positive feedback via GAB1 and IRS. We demonstrate that GAB1 behaves as a non‐linear amplifier of mitogenic responses and insulin endows EGF signaling with robustness to GAB1 suppression. Our results show the feasibility of using computational models to identify key target combinations and predict complex cellular responses to a mixture of external cues.https://doi.org/10.1038/msb.2009.19computational modelingcrosstalkepidermal growth factor receptorinsulin receptornetworks |
| spellingShingle | Nikolay Borisov Edita Aksamitiene Anatoly Kiyatkin Stefan Legewie Jan Berkhout Thomas Maiwald Nikolai P Kaimachnikov Jens Timmer Jan B Hoek Boris N Kholodenko Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling Molecular Systems Biology computational modeling crosstalk epidermal growth factor receptor insulin receptor networks |
| title | Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling |
| title_full | Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling |
| title_fullStr | Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling |
| title_full_unstemmed | Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling |
| title_short | Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling |
| title_sort | systems level interactions between insulin egf networks amplify mitogenic signaling |
| topic | computational modeling crosstalk epidermal growth factor receptor insulin receptor networks |
| url | https://doi.org/10.1038/msb.2009.19 |
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