Receptor-Based Mechanism of Relative Sensing in Mammalian Signaling Networks

Mammalian cells operate in fluctuating environments by perceiving and reacting to a diverse set of extracellular stimuli. Detecting relative rather than absolute changes in their environments may enable cells to make decisions in diverse biological contexts. However, precise molecular mechanisms underlying such relative sensing by mammalian signaling networks are not well understood. Here we use a combined computational and experimental analysis to investigate the growth factor activated immediate-early phosphorylation response of protein kinase B (Akt). We demonstrate that activity-dependent receptor degradation allows cells to robustly detect fold changes in extracellular Epidermal Growth Factor (EGF) levels across orders of magnitude of EGF background concentrations. Interestingly, we show that the memory of the background stimulation is effectively encoded in the number of EGF receptors on the cell surface. We further demonstrate that the ability to sense relative changes by the Akt pathway extends to hepatocyte growth factor (HGF) signaling. We develop an analytical model that reveals key aggregate network parameters controlling the relative sensing capabilities of the system. The mechanism described in our study could play a role in multiple other sensory cascades where stimulation leads to a proportional reduction in the abundance of cell surface receptors. Beyond simple receptor and signal downregulation, this mechanism may allow cells to continuously monitor their environments and store the memory of past ligand exposures.