Perfect and Near-Perfect Adaptation in Cell Signaling

Ferrell, James E.

doi:10.1016/j.cels.2016.02.006

Cited by 156 publications

(206 citation statements)

References 29 publications

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“…Our observations suggest a rationale for why centriole biogenesis may be regulated by an oscillatory system: in the model we describe here, Asl functions as an integrator (Ferrell, 2016;Somvanshi et al, 2015) whose levels are kept constant so that the oscillator can monitor changes in the input (in this case, cytoplasmic Plk4 levels) and respond accordingly by adapting the oscillation to maintain a constant output (in this case, centriole size). If this is correct, the Plk4 oscillator should be able to adapt to changes in Plk4 levels to maintain a consistent centriole size, but not to changes in Asl levels.…”

Section: Resultsmentioning

confidence: 95%

A free-running oscillator times and executes centriole biogenesis

Aydogan

Steinacker

Mofatteh

et al. 2019

Preprint

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Section: Resultsmentioning

confidence: 95%

A free-running oscillator times and executes centriole biogenesis

Aydogan

Steinacker

Mofatteh

et al. 2019

Preprint

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“…The perfect and near perfect adaptation we observed for the UPS implies the existence of an underlying network that can mechanistically achieve this (Ferrell 2016). In the case of folding stress, RPN4 is activated transcriptionally ( Figure 4B and 4C), likely by Hsf1, to achieve perfect adaptation for proteins that aggregate in the cytosol.…”

Section: Discussionmentioning

confidence: 82%

Quantitative analysis of the ubiquitin-proteasome system under proteolytic and folding stressors

Jj¹,

Brandman²

2019

Preprint

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Aging, disease, and environmental stress are associated with failures in the ubiquitinproteasome system (UPS), yet a quantitative understanding of how the UPS responds to stress conditions is lacking. Here we assessed the performance and adaptability of the UPS in yeast under stress conditions using quantitative measurements of misfolded substrate stability and stress-dependent UPS regulation by the transcription factor Rpn4. We found that impairing degradation rates ("proteasomal stress") and generating misfolded proteins ("folding stress") stabilized UPS substrates through separate, non-overlapping mechanisms. Folding stress stabilized proteins by causing aggregation rather than targeting to the proteasome and increasing overall proteasomal load. Despite differences in underlying proteostasis defects, the UPS productively adapted to both proteasomal and folding stressors using separate mechanisms of Rpn4 activation, in some cases resulting in no loss in UPS substrate degradation. Our work reveals the distinct effects of proteotoxic stressors and the versatility of cells in productively adapting the UPS. ____________________________________________________________________________

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“…Receptor endocytosis and down-regulation following ligand stimulation has been canonically associated with signal desensitization (15)(16)(17). Our analysis suggests a specific quantitative role for receptors downregulation: it may allow cells to continuously monitor signals in their environment (18)(19)(20) and respond to relative changes in environmental stimuli.…”

mentioning

confidence: 76%

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

Lyashenko

Niepel

Dixit

et al. 2017

Preprint

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Mammalian cells operate in fluctuating environments by perceiving and reacting to a diverse set of extracellular stimuli 1 . Detecting relative rather than absolute changes in their environments may enable cells to make decisions in diverse biological contexts 2,3 .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.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. To understand how the immediate-early dynamics of the EGFR/Akt pathway depends on the background level of EGF we used immunofluorescence to quantify the pAkt signal in human non-transformed mammary epithelial MCF10A cells (SI section II).In agreement with previous studies 9 , upon continuous stimulation with EGF, pAkt Prior exposure with EGF desensitized cells to subsequent EGF stimulations in a quantitative manner, i.e. maximal pAkt response to the same EGF stimulation (2 ng/ml) was monotonically attenuated with increasing pre-exposure EGF levels ( Figure 1d).These results suggest that the strength of the pAkt responses to EGF stimulation is modulated by background EGF levels and that this effect is mediated by the removal of activated EGFRs from cell surface 10 .peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/158774 doi: bioRxiv preprint first posted online Jul. 2, 2017; Table 1), and fitted the model using pAkt time courses and steady state sEGFR levels at different doses of EGF stimulations. Parameter optimization was performed using simulated annealing (SA) 15 (SI section III). Parameters of ODE models describing complex signaling networks are usually underdetermined with multiple distinct parameter sets producing similar fits to the data 16 . Th...

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Perfect and Near-Perfect Adaptation in Cell Signaling

Cited by 156 publications

References 29 publications

A free-running oscillator times and executes centriole biogenesis

A free-running oscillator times and executes centriole biogenesis

Quantitative analysis of the ubiquitin-proteasome system under proteolytic and folding stressors

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

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