Predictive data-driven modeling of C-terminal tyrosine function in the EGFR signaling network

The Epidermal Growth Factor Receptor (EGFR) has been studied extensively due to its critical role in cellular signaling and association with disease. Previous models have elucidated interactions between EGFR and downstream adaptor proteins, or showed phenotypes affected by EGFR. However, the link between EGFR phosphorylation and phenotypic outcome is still poorly understood. Here, we employed a suite of isogenic cells lines expressing site-specific mutations at each of the EGFR C-terminal phosphorylation sites to interrogate their role in signaling network and cell biological response to stimulation. Our results demonstrate the resilience of the EGFR network, which was largely similar even in the context of multiple Y-to-F mutations in the EGFR C-terminal tail, while also revealing nodes in the network that have not previously been linked to EGFR signaling. Our data-driven model highlights signaling network nodes associated with distinct EGF-driven cell responses, including migration, proliferation, and receptor trafficking. Application of this same approach to less studied RTKs should provide a plethora of novel associations that should lead to a much better understanding of these signaling networks.