ArticleBMC bioinformatics2019
Time-dependent antagonist-agonist switching in receptor tyrosine kinase-mediated signaling.
Article in BMC bioinformatics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 6 citations in OpenAlex.
- miR-380-3p promotes β-casein expression by targeting αS1-casein in goat mammary epithelial cells.Animal bioscience · 2023Article
- Mutation of Signal Transducer and Activator of Transcription 5 (STAT5) Binding Sites Decreases Milk Allergen αFoods (Basel, Switzerland) · 2022Article
- Genistein Directly Represses the Phosphorylation of STAT5 in Lactating Mammary Epithelial Cells.ACS omega · 2021Article
- Membrane signalosome: where biophysics meets systems biology.Current opinion in systems biology · 2021Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundErbB4/HER4 is a unique member of the ErbB family of receptor tyrosine kinases concerning its activation of anti-proliferative JAK2-STAT5 pathway when stimulated by ligand Neuregulin (NRG). Activation of this pathway leads to expression of genes like β-casein which promote cell differentiation. Recent experimental studies on mouse HC11 mammary epithelial cells stimulated by ligand Neuregulin (NRG) showed a time-dependent switching behavior in the β-casein expression. This behavior cannot be explained using currently available mechanistic models of the JAK-STAT pathway. We constructed an improved mechanistic model which introduces two crucial modifications to the canonical HER4-JAK2-STAT5 pathway based on literature findings. These modifications include competitive HER4 heterodimerization with other members of the ErbB family and a slower JAK2 independent activation STAT5 through HER4. We also performed global sensitivity analysis on the model to test the robustness of the predictions and parameter combinations that are sensitive to the outcome.
resultsOur model was able to reproduce the time-dependent switching behavior of β-casein and also establish that the modifications mentioned above to the canonical JAK-STAT pathway are necessary to reproduce this behavior. The sensitivity studies show that the competitive HER4 heterodimerization reactions have a profound impact on the sensitivity of the pathway to NRG stimulation, while the slower JAK2-independent pathway is necessary for the late stage promotion of β-casein mRNA transcription. The difference in the time scales of the JAK-dependent and JAK-independent pathways was found to be the main contributing factor to the time-dependent switch. The transport rates controlling activated STAT5 dimer nuclear import and β-casein mRNA export to cytoplasm affected the time delay between NRG stimulation and peak β-casein mRNA activity.
conclusionThis study highlights the effect of competitive and parallel reaction pathways on both short and long-term dynamics of receptor-mediated signaling. It provides robust and testable predictions of the dynamical behavior of the HER4 mediated JAK-STAT pathway which could be useful in designing treatments for various cancers where this pathway is activated/altered.
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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 Socratic graph.