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

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.