(172e) Receptor Endoyctosis and Cell Memory in Growth Factor Signaling

Cells need to sense and respond to signals in a constantly changing environment. Responding to relative rather than absolute changes in the stimuli enables cells to remain sensitive over a wide range of background signal levels. Indeed, various biological systems ranging from bacterial chemotaxis to human sensory perception systems, such as vision, are known to respond to relative changes in their environment. With a combined modeling and experimental approach we identify a novel mechanism of relative sensing of extracellular ligands by mammalian signaling cascades. Specifically, we study the epidermal growth factor (EGF) induced signaling cascade and demonstrate that the pathways’ immediate-early phosphorylation response can sense relative change in extracellular level of EGF. Using a theoretical model, we analytically explain the mechanism of relative sensing by deriving constraints on the network parameters and confirm their consistency with the values derived through fitting experimental phospho-proteomic data. Importantly, the derived constraints are characteristic of multiple other signaling cascades. This points to the potential generality of the discovered phenomenon of extracellular ligand relative sensing across many other signaling systems. Overall, our work presents a novel quantitative framework to understand how cells respond to fluctuating environments in vivo.