Cell surface receptors are activated by binding of ligand molecules and communicate signals from outside to inside the cell. EGF receptor (EGFR) signaling is broadly associated with cell growth, differentiation, and migration, and linked to many cancers. Recent experiments demonstrated that EGFR activation is spatially restricted, with receptors primarily binding ligands when localized to tetraspanin nanodomains on the cell membrane. We use kinetic modeling of receptor location, ligand binding, and internalization to understand the effect of this spatial restriction on signaling by comparing a localized receptor activation model that enhances ligand binding within specific regions (tetraspanin nanodomains) to a conventional receptor model that binds ligand anywhere on the cell membrane. We find that localized receptor activation shifts steady-state signaling to higher ligand concentrations, effectively suppressing signaling. Similarly, localized receptor activation alters the response to sudden ligand concentration increases, flattening and extending the signaling peak, representing suppression of signal strength and enhancement of signal duration compared to the receptors without locally enhanced activation. We also find that multiple experimental signaling timescales for different ligand types are consistent with our spatial activation model and inconsistent with the conventional receptor model. EGFR form dimers as part of their signaling pathway; our modeling shows that the spatial activation model shifts peak dimer levels to higher ligand binding rates. These results suggest that locally-enhanced activation in tetraspanin nanodomains allows the cell to tune its signaling response. This modeling of spatially restricted activation builds toward physical principles of cell surface signaling.
Duong et al. (Sun,) studied this question.