ERK activation is enhanced by the scaffolding proteins KSR and MP1, localized 
near the cell membrane and late endosomes respectively, but little is known 
about their dynamic interplay. We develop here a mathematical model with 
ordinary differential equations to describe the dynamic activation of EGFR-ERK 
signaling under a conventional pathway without scaffolds, a KSR-scaffolded 
pathway, and an MP1-scaffolded pathway, and their impacts were examined under 
the influence of the endosomal regulators, Cbl-CIN85 and Endophilin A1. This new 
integrated model, validated against experimental results and computational 
constraints, shows that changes of ERK activation and EGFR endocytosis in 
response to EGF concentrations (i.e ligand sensitivity) depend on these scaffold 
proteins and regulators. The KSR-scaffolded and the conventional pathways act 
synergistically and are sensitive to EGF stimulation. When the KSR level is 
high, the sensitivity of ERK activation from this combined pathway remains low 
when Cbl-CIN85 level is low. But, such sensitivity can be increased with 
increasing levels of Endophilin if Cbl-CIN85 level becomes high. However, 
reduced KSR levels already present high sensitivity independent of Endophilin 
levels. In contrast, ERK activation by MP1 is additive to that of KSR but it 
shows little ligand-sensitivity under high levels of EGF. This can be partly 
reversed by increasing level of Endophilin while keeping Cbl-CIN85 level low. 
Further analyses showed that high levels of KSR affect ligand-sensitivity of 
EGFR endocytosis whereas MP1 ensures the robustness of endosomal ERK activation. 
These simulations constitute a multi-dimensional exploration of how 
EGF-dependent EGFR endocytosis and ERK activation are dynamically affected by 
scaffolds KSR and MP1, co-regulated by Cbl-CIN85 and Endophilin A1. Together, 
these results provide a detailed and quantitative demonstration of how 
regulators and scaffolds can collaborate to fine-tune the ligand-dependent 
sensitivity of EGFR endocytosis and ERK activation which could underlie 
differences during normal physiology, disease states and drug responses.