Time-dependent antagonist-agonist switching in receptor tyrosine kinase-mediated signaling

BMC Bioinformatics

Ravi Radhakrishnan¹  Alokendra Ghosh² 

[1] 0000 0004 1936 8972, grid.25879.31, Department of Bioengineering, University of Pennsylvania, Philadelphia, USA;0000 0004 1936 8972, grid.25879.31, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, USA;

关键词: RTK signaling;    JAK-STAT pathway;    Time-dependent switch;    Global sensitivity;   

DOI  :  10.1186/s12859-019-2816-3

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY