Receptor-based mechanism of relative sensing and cell memory in mammalian signaling networks

Abstract

Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in fluctuating environments. However, how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, i.e. perform fold change detection, is not well understood. Using the growth factor-activated PI3K-Akt signaling pathway, we develop computational and analytical models, and experimentally validate a novel mechanism of relative sensing in mammalian cells. This mechanism relies on a new form of cellular memory, where cells effectively encode past stimulation levels in the abundance of cognate receptors on the cell surface. We show the robustness and specificity of the relative sensing for two physiologically important ligands, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and across wide ranges of background stimuli. Our results suggest that similar mechanisms of memory and fold change detection are likely to be important across diverse signaling cascades and biological contexts.