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 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.

Epidermal Growth Factor Tethered through Coiled-Coil Interactions Induces Cell Surface Receptor Phosphorylation

2009 ◽  
Vol 20 (8) ◽  
pp. 1569-1577 ◽  
Author(s):  
Cyril Boucher ◽  
Benoît Liberelle ◽  
Mario Jolicoeur ◽  
Yves Durocher ◽  
Gregory De Crescenzo
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Coiled Coil ◽  
Cell Surface Receptor ◽  
Receptor Phosphorylation ◽  
Surface Receptor ◽  
Epidermal Growth

An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway

1994 ◽  
Vol 14 (1) ◽  
pp. 663-675
Author(s):  
M Santoro ◽  
W T Wong ◽  
P Aroca ◽  
E Santos ◽  
B Matoskova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Egf Receptor ◽  
Biological Effects ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Dependent Signal ◽  
Epidermal Growth

A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.

scholarly journals Laminin γ3 Chain Binds to Nidogen and Is Located in Murine Basement Membranes

2005 ◽  
Vol 280 (23) ◽  
pp. 22146-22153 ◽  
Author(s):  
Nikolaus Gersdorff ◽  
Eddie Kohfeldt ◽  
Takako Sasaki ◽  
Rupert Timpl ◽  
Nicolai Miosge
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Self Assembly ◽  
Mammalian Cells ◽  
Polyclonal Antibodies ◽  
Basement Membranes ◽  
Electron Microscopic ◽  
Immunogold Staining ◽  
Adult Mice ◽  
Epidermal Growth

Recently a novel laminin γ3 chain was identified in mouse and human and shown to have the same modular structure as the laminin γ1 chain. We expressed two fragments of the γ3 chain in mammalian cells recombinantly. The first, domain VI/V, consisting of laminin N-terminal (domain VI) and four laminin-type epidermal growth factor-like (domain V) and laminin N-terminal modules, was shown to be essential for self-assembly of laminins. The other was domain III3–5, which consists of three laminin-type epidermal growth factor-like modules and is predicted to bind to nidogens. The γ3 VI/V fragment was a poor inhibitor for laminin-1 polymerization as was the β2 VI/V fragment. The γ3 III3–5 fragment bound to nidogen-1 and nidogen-2 with lower affinity than the γ1 III3–5 fragment. These data suggested that laminins containing the γ3 chain may assemble networks independent of other laminins. Polyclonal antibodies raised against γ3 VI/V and γ3 III3–5 showed no cross-reaction with homologous fragments from the γ1 and γ2 chains of laminin and allowed the establishment of γ chain-specific radioimmunoassays and light and electron microscopic immunostaining of tissues. This demonstrated a 20–100-fold lower content of the γ3 chain compared with the γ1 chain in various tissue extracts of adult mice. The expression of γ3 chain was highly tissue-specific. In contrast to earlier assumptions, the antibodies against the γ3 chain showed light microscopic staining exclusively in basement membrane zones of adult and embryonic tissues, such as the brain, kidney, skin, muscle, and testis. Ultrastructural immunogold staining localized the γ3 chain to basement membranes of these tissues.

scholarly journals An empirical bayesian approach for testing gene expression fold change and its application in detecting global dosage effects

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Zhenxing Guo ◽  
Ying Cui ◽  
Xiaowen Shi ◽  
James A Birchler ◽  
Igor Albizua ◽  
...  
Keyword(s):  
Gene Expression ◽  
Change Detection ◽  
Bayesian Approach ◽  
Variance Estimation ◽  
T Test ◽  
Fold Change ◽  
Empirical Bayesian ◽  
Biological Studies ◽  
Fold Change Detection ◽  
Empirical Bayesian Approach

Abstract We are motivated by biological studies intended to understand global gene expression fold change. Biologists have generally adopted a fixed cutoff to determine the significance of fold changes in gene expression studies (e.g. by using an observed fold change equal to two as a fixed threshold). Scientists can also use a t-test or a modified differential expression test to assess the significance of fold changes. However, these methods either fail to take advantage of the high dimensionality of gene expression data or fail to test fold change directly. Our research develops a new empirical Bayesian approach to substantially improve the power and accuracy of fold-change detection. Specifically, we more accurately estimate gene-wise error variation in the log of fold change. We then adopt a t-test with adjusted degrees of freedom for significance assessment. We apply our method to a dosage study in Arabidopsis and a Down syndrome study in humans to illustrate the utility of our approach. We also present a simulation study based on real datasets to demonstrate the accuracy of our method relative to error variance estimation and power in fold-change detection. Our developed R package with a detailed user manual is publicly available on GitHub at https://github.com/cuiyingbeicheng/Foldseq.

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