Frequency modulation of <scp>ERK</scp> activation dynamics rewires cell fate

Ryu, Hyunryul; Chung, Minhwa; Dobrzyński, Maciej; Fey, Dirk; Blum, Yannick; Lee, Sung Sik; Peter, Matthias; Kholodenko, Boris N.; Jeon, Noo Li; Pertz, Olivier

doi:10.15252/msb.20166982

Cited by 37 publications

(43 citation statements)

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“…Our model demonstrates that a remarkably simple network – a single negative feedback loop, coupled to target gene promoters with different sensitivities to Erk – enables target genes to act as tunable band-pass filters that respond to specific frequencies of Ras pulses. The frequency of upstream stimuli may thus be decoded into distinct cellular responses, consistent with recent studies showing that pulsatile NGF stimulation induces more homogenous differentiation in PC-12 cells than does continuous stimulation (Ryu et al, 2016), as well as by the finding that certain frequencies of osmolarity stress dramatically reduce yeast cell growth (Mitchell et al, 2015). Future studies combining precise optogenetic stimuli and reporters of cell fate could shed new light on whether the dynamics of a single pathway are sufficient to distinguish among cell fate responses.…”

Section: Discussionsupporting

confidence: 79%

Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control

et al. 2017

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Summary Cell signaling networks coordinate specific patterns of protein expression in response to external cues. Yet the logic by which signaling pathway activity determines the eventual abundance of target proteins is complex and poorly understood. Here, we describe an approach for simultaneously controlling the Ras/Erk pathway while monitoring a target gene’s transcription and protein accumulation in single live cells. We apply our approach to dissect how Erk activity is decoded by immediate-early genes (IEGs). We find that IEG transcription decodes Erk dynamics through a shared band-pass filtering circuit: repeated Erk pulses transcribe IEGs more efficiently than sustained Erk inputs. However, despite highly similar transcriptional responses, each IEG exhibits dramatically different protein-level accumulation, demonstrating a high degree of post-transcriptional regulation by combinations of multiple pathways. Our results demonstrate that the Ras/Erk pathway is decoded both by dynamic filters and logic gates to shape target gene responses in a context-specific manner.

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Section: Discussionsupporting

confidence: 79%

Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control

et al. 2017

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“…Several computational models have been developed that can predict the behaviour of RTKs and their downstream signalling pathways (Ryu et al, ; Adlung et al, ), including those that have been adapted to predict optimal combination therapies in an attempt to overcome resistance to RTK inhibitors. Invariably, these models are developed and calibrated under standard conditions using data derived from cancer cell lines grown on tissue culture plastic.…”

Section: Potential Applications For Modelling Of Matrix Signallingmentioning

confidence: 99%

“…A number of elegant models have been developed to describe the dynamics of MAPK signalling, in which a key regulatory mechanism is the negative feedback and crosstalk that occurs through both rapid, phosphorylation‐based inhibition of upstream signalling components, and slower transcriptional induction of negative regulators (Kholodenko et al, ; Bluthgen, ; Ryu et al, ). This dynamic network rewiring strongly regulates the temporal kinetics of each discrete MAPK but also generates feedback‐based network structures that can influence the sensitivity and dynamic behaviour of all MAPK pathways (Fey et al, ).…”

Section: Potential Applications For Modelling Of Matrix Signallingmentioning

confidence: 99%

The extracellular matrix as a key regulator of intracellular signalling networks

Hastings

Skhinas

Fey

et al. 2018

British J Pharmacology

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167

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The extracellular matrix (ECM) is a salient feature of all solid tissues within the body. This complex, acellular entity is composed of hundreds of individual molecules whose assembly, architecture and biomechanical properties are critical to controlling the behaviour and phenotype of the different cell types residing within tissues. Cells are the basic unit of life and the core building block of tissues and organs. At their simplest, they follow a set of rules, governed by their genetic code and effected through the complex protein signalling networks that these genes encode. These signalling networks assimilate and process the information received by the cell to control cellular decisions that govern cell fate. The ECM is the biggest provider of external stimuli to cells and as such is responsible for influencing intracellular signalling dynamics. In this review, we discuss the inclusion of ECM as a central regulatory signalling sub-network in computational models of cellular decision making, with a focus on its role in diseases such as cancer. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

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“…For example, in rat PC12 cells, sustained epidermal growth factor (EGF) stimulation of ERK signaling was found to induce proliferation, while sustained nerve growth factor (NGF) stimulation resulted in differentiation . In contrast, when pulses of low EGF concentrations were applied to the cells, they underwent differentiation instead, while pulses of higher EGF concentrations resulted in proliferation …”

Section: Erk Pathway Signaling Dynamicsmentioning

confidence: 99%

Targeting ERK beyond the boundaries of the kinase active site in melanoma

Sammons

Ghose

Tsai

et al. 2019

Molecular Carcinogenesis

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Extracellular signal‐regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF‐V600E mutant melanoma, ERK inhibition has emerged as a viable clinical approach to abrogate signaling through the ERK pathway, even in cases where MEK and Raf inhibitor treatments fail to induce tumor regression due to resistance mechanisms. Several ERK inhibitors that target the active site of ERK have reached clinical trials, however, many critical ERK interactions occur at other potentially druggable sites on the protein. Here we discuss the role of ERK signaling in cell fate, in driving melanoma, and in resistance mechanisms to current BRAF‐V600E melanoma treatments. We explore targeting ERK via a distinct site of protein‐protein interaction, known as the D‐recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF‐V600E melanoma. Targeting the DRS with inhibitors in melanoma has the potential to not only disrupt the catalytic apparatus of ERK but also its noncatalytic functions, which have significant impacts on spatiotemporal signaling dynamics and cell fate.

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Frequency modulation of ERK activation dynamics rewires cell fate

Cited by 37 publications

References 0 publications

Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control

Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control

The extracellular matrix as a key regulator of intracellular signalling networks

Targeting ERK beyond the boundaries of the kinase active site in melanoma

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