ArticleMolecular systems biology2009
Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.
Article in Molecular systems biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed, 223 citations in OpenAlex.
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- Mathematical Modeling and Inference of Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Cell Signaling Pathways.International journal of molecular sciences · 2024Review
- A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.Cell reports · 2023Article
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- Modeling Cellular Signaling Variability Based on Single-Cell Data: The TGFβ-SMAD Signaling Pathway.Methods in molecular biology (Clifton, N.J.) · 2023Review
- Insulin Resistance and Acne: The Role of Metformin as Alternative Therapy in Men.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Relating individual cell division events to single-cell ERK and Akt activity time courses.Scientific reports · 2022Article
- Control of cell state transitions.Nature · 2022Article
- Structural insights into Ras regulation by SIN1.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Potential and Therapeutic Roles of Diosmin in Human Diseases.Biomedicines · 2022Review
- OncoboxPD: human 51 672 molecular pathways database with tools for activity calculating and visualization.Computational and structural biotechnology journal · 2022Article
- Concentrated growth factor regulates the macrophage-mediated immune response.Regenerative biomaterials · 2021Article
- Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.Endocrinology · 2021Article
- Programmed Death-Ligand 1 (PD-L1) Expression Is Induced by Insulin in Pancreatic Ductal Adenocarcinoma Cells Pointing to Its Role in Immune Checkpoint Control.Medical sciences (Basel, Switzerland) · 2021Article
- Inhibition of RPS6K reveals context-dependent Akt activity in luminal breast cancer cells.PLoS computational biology · 2021Article
51 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
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 (PIP(3)) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin-induced amplification of mitogenic signaling is abolished by disrupting PIP(3)-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.