scholarly journals Receptor-Based Mechanism of Cell Memory and Relative Sensing in Mammalian Signaling Networks

2017 ◽  
Author(s):  
Eugenia Lyashenko ◽  
Mario Niepel ◽  
Purushottam D. Dixit ◽  
Sang Kyun Lim ◽  
Peter K. Sorger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Mammalian Cells ◽  
Analytical Models ◽  
Signaling Networks ◽  
Surface Receptors ◽  
Epidermal Growth ◽  
External Signals ◽  
Hepatocyte Growth ◽  
Proportional Reduction

AbstractDetecting relative rather than absolute changes in external signals enables cells to make decisions in fluctuating environments and diverse biological contexts. However, how mammalian signaling networks store the memories of past stimuli and use them to compute relative signals 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 non-transcriptional 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. The described memory and sensing mechanism could play a role in multiple other sensory cascades where stimulation leads to a proportional reduction in the abundance of cell surface receptors.

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Eugenia Lyashenko ◽  
Mario Niepel ◽  
Purushottam D Dixit ◽  
Sang Kyun Lim ◽  
Peter K Sorger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Change Detection ◽  
Mammalian Cells ◽  
Fold Change ◽  
Analytical Models ◽  
Signaling Networks ◽  
Cell Memory ◽  
Surface Receptor ◽  
Epidermal Growth ◽  
Fold Change Detection

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.

scholarly journals The Na+/H+ Exchanger Regulatory Factor Stabilizes Epidermal Growth Factor Receptors at the Cell Surface

2004 ◽  
Vol 15 (12) ◽  
pp. 5470-5480 ◽  
Author(s):  
Cheri S. Lazar ◽  
Catherine M. Cresson ◽  
Douglas A. Lauffenburger ◽  
Gordon N. Gill
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Growth Factor Receptors ◽  
Cell Surface Receptors ◽  
Epidermal Growth Factor Receptors ◽  
Regulatory Factor ◽  
Down Regulation ◽  
Surface Receptors ◽  
Epidermal Growth

Ligand binding to cell surface receptors initiates both signal transduction and endocytosis. Although signaling may continue within the endocytic compartment, down-regulation is the major mechanism that controls the concentration of cell surface receptors, their ability to receive environmental signals, and the ultimate strength of biological signaling. Internalization, recycling, and trafficking of receptor tyrosine kinases (RTKs) within the endosome compartment are each regulated to control the overall process of down-regulation. We have identified the Na+/H+ exchanger regulatory factor (NHERF) as an important molecular component that stabilizes epidermal growth factor receptors (EGFRs) at the cell surface to restrict receptor down-regulation. The NH2-terminal PDZ domain (PDZ 1) of NHERF specifically binds to an internal peptide motif located within the COOH-terminal regulatory domain of EGFR. Expression of NHERF slows the rate of EGF-induced receptor degradation. A point mutation that abolishes the PDZ 1 recognition sequence of EGFR enhances the rate of ligand-induced endocytosis and down-regulation of EGFR. Similarly, expression of a dominant negative mutant of NHERF enhances EGF-induced receptor down-regulation. In contrast to β-adrenergic receptors where NHERF enhances recycling of internalized receptors, NHERF stabilizes EGFR at the cell surface and slows the rate of endocytosis without affecting recycling. Although the mechanisms differ, for both RTKs and G protein-coupled receptors, the overall effect of NHERF is to enhance the fraction of receptors present at the cell surface.

Developing Concepts in Receptor Research

1983 ◽  
Vol 17 (5) ◽  
pp. 357-366 ◽  
Author(s):  
Pedro Cuatrecasas
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Cell Biology ◽  
Protein Chemistry ◽  
Coated Pits ◽  
Surface Receptors ◽  
Epidermal Growth ◽  
Receptor Research ◽  
Receptor Assays

Recent advances in molecular biology and protein chemistry have permitted spectacular progress in understanding the chemistry and cell biology of cell surface receptors for hormones and drugs. Methodological approaches, such as the use of radiolabeled ligands and direct receptor assays, have permitted the characterization, categorization, and purification of many receptors. The knowledge gained in understanding fundamental hormone-receptor interactions can form the basis of future, rational new drug design. Another important advance relates to the dynamic nature of receptors in their membrane environment. Upon binding of hormones such as insulin and epidermal growth factor, the complexes rearrange topographically on the cell surface, forming microclusters that are internalized into “receptosomes” via receptor-mediated endocytosis (which utilizes coated pits). The internalized receptor-hormone complex can have various fates, including the generation of selective signals for controlling cell growth and differentiation. In at least one case (epidermal growth factor), the latter may be dependent on the processes that occur in an acidic endosomal compartment within the cell.

Thrombin and epidermal growth factor become linked to cell surface receptors during mitogenic stimulation

Nature ◽  
1979 ◽  
Vol 278 (5706) ◽  
pp. 743-745 ◽  
Author(s):  
JOFFRE B. BAKER ◽  
ROBERT L. SIMMER ◽  
KEVIN C. GLENN ◽  
DENNIS D. CUNNINGHAM
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Cell Surface Receptors ◽  
Mitogenic Stimulation ◽  
Surface Receptors ◽  
Epidermal Growth
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