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

eLife

Sang Kyun Lim¹  Eugenia Lyashenko²  Purushottam D Dixit²  Dennis Vitkup²  Peter K Sorger³  Mario Niepel³ 

[1] Department of Physics, University of Florida, Gainesville, United States;Department of Systems Biology, Columbia University, New York, United States;HMS LINCS Center Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, United States;

关键词: relative sensing;    receptor endocytosis;    EGFR;    cell memory;    signaling networks;   

DOI  :  10.7554/eLife.50342

来源: DOAJ

【 摘 要 】

Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in constantly fluctuating environments. It is currently not well understood how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, that is perform fold change detection. Using the growth factor-activated PI3K-Akt signaling pathway, we develop here computational and analytical models, and experimentally validate a novel non-transcriptional 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. The surface receptor abundance is regulated by background signal-dependent receptor endocytosis and down-regulation. We show the robustness and specificity of 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 cell memory and fold change detection may be important in diverse signaling cascades and multiple biological contexts.

【 授权许可】

Unknown