scholarly journals Temporal perturbation of Erk dynamics reveals network architecture of FGF2-MAPK signaling

2019 ◽  
Author(s):  
Yannick Blum ◽  
Jan Mikelson ◽  
Maciej Dobrzyński ◽  
Hyunryul Ryu ◽  
Marc-Antoine Jacques ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Population ◽  
Network Architecture ◽  
Population Distribution ◽  
Population Level ◽  
Mapk Signaling ◽  
Erk Signaling ◽  
Signaling Dynamics ◽  
Temporal Perturbation ◽  
Erk Activity

AbstractStimulation of PC-12 cells with epidermal (EGF) versus nerve (NGF) growth factors (GFs) biases the distribution between transient and sustained single-cell ERK activity states, and between proliferation and differentiation fates within a cell population. We report that fibroblast GF (FGF2) evokes a distinct behavior that consists of a gradually changing population distribution of transient/sustained ERK signaling states in response to increasing inputs in a dose response. Temporally-controlled GF perturbations of MAPK signaling dynamics applied using microfluidics reveals that this wider mix of ERK states emerges through the combination of an intracellular feedback, and competition of FGF2 binding to FGF receptors (FGFR) and heparan-sulfate proteoglycans (HSPGs) co-receptors. We show that the latter experimental modality is instructive for model selection using a Bayesian parameter inference. Our results provide novel insights into how different receptor tyrosine kinase (RTK) systems differentially wire the MAPK network to fine tune fate decisions at the cell population-level.Microfluidics, Erk Signaling Dynamics, Mechanistic Modelling, Parameter Estimation, Cell Fate Determination

scholarly journals Temporal perturbation of ERK dynamics reveals network architecture of FGF2/MAPK signaling

2019 ◽  
Vol 15 (11) ◽  
Author(s):  
Yannick Blum ◽  
Jan Mikelson ◽  
Maciej Dobrzyński ◽  
Hyunryul Ryu ◽  
Marc‐Antoine Jacques ◽  
...  
Keyword(s):  
Network Architecture ◽  
Mapk Signaling ◽  
Temporal Perturbation

scholarly journals Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics

2020 ◽  
Vol 13 (645) ◽  
pp. eaaz5267 ◽  
Author(s):  
Anatoly Kiyatkin ◽  
Iris K. van Alderwerelt van Rosenburgh ◽  
Daryl E. Klein ◽  
Mark A. Lemmon
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Egf Receptor ◽  
Receptor Internalization ◽  
Erk Signaling ◽  
Activation Kinetics ◽  
Kinase Activation ◽  
Erk Activation ◽  
Cell Fate Decisions ◽  
Signaling Dynamics

In responses to activation of receptor tyrosine kinases (RTKs), crucial cell fate decisions depend on the duration and dynamics of ERK signaling. In PC12 cells, epidermal growth factor (EGF) induces transient ERK activation that leads to cell proliferation, whereas nerve growth factor (NGF) promotes sustained ERK activation and cell differentiation. These differences have typically been assumed to reflect distinct feedback mechanisms in the Raf-MEK-ERK signaling network, with the receptors themselves acting as simple upstream inputs. We failed to confirm the expected differences in feedback type when investigating transient versus sustained signaling downstream of the EGF receptor (EGFR) and NGF receptor (TrkA). Instead, we found that ERK signaling faithfully followed RTK dynamics when receptor signaling was modulated in different ways. EGFR activation kinetics, and consequently ERK signaling dynamics, were switched from transient to sustained when receptor internalization was inhibited with drugs or mutations, or when cells expressed a chimeric receptor likely to have impaired dimerization. In addition, EGFR and ERK signaling both became more sustained when substoichiometric levels of erlotinib were added to reduce duration of EGFR kinase activation. Our results argue that RTK activation kinetics play a crucial role in determining MAP kinase cascade signaling dynamics and cell fate decisions, and that signaling outcome can be modified by activating a given RTK in different ways.

scholarly journals Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 513 ◽  
Author(s):  
Yu Muta ◽  
Michiyuki Matsuda ◽  
Masamichi Imajo
Keyword(s):  
Cell Fate ◽  
Cellular Responses ◽  
Erk Signaling ◽  
Biological Processes ◽  
Cell Level ◽  
Erk Activation ◽  
Cell Fate Decisions ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Erk Activity

The extracellular signal-regulated kinase (ERK) signaling pathway regulates a variety of biological processes including cell proliferation, survival, and differentiation. Since ERK activation promotes proliferation of many types of cells, its deregulated/constitutive activation is among general mechanisms for cancer. Recent advances in bioimaging techniques have enabled to visualize ERK activity in real-time at the single-cell level. Emerging evidence from such approaches suggests unexpectedly complex spatiotemporal dynamics of ERK activity in living cells and animals and their crucial roles in determining cellular responses. In this review, we discuss how ERK activity dynamics are regulated and how they affect biological processes including cell fate decisions, cell migration, embryonic development, tissue homeostasis, and tumorigenesis.

scholarly journals Signaling dynamics control cell fate in the early Drosophila embryo

2018 ◽  
Author(s):  
Heath E. Johnson ◽  
Stanislav Y. Shvartsman ◽  
Jared E. Toettcher
Keyword(s):  
Cell Fate ◽  
Time Window ◽  
Activity Patterns ◽  
Control Cell ◽  
High Amplitude ◽  
Mitogen Activated Protein Kinase ◽  
Drosophila Embryo ◽  
Erk Signaling ◽  
Early Drosophila Embryo ◽  
Erk Activity

The Erk mitogen-activated protein kinase plays diverse roles in animal development, where its activity is associated with phenomena including cell migration, proliferation and differentiation. Its widespread reuse raises a conundrum: when a single kinase like Erk is activated, how does a developing cell know which fate to adopt? Here, we combine precise optogenetic control with genetic perturbations to dissect Erk-dependent cellular responses in the early Drosophila embryo. We find that light-stimulated Erk activity is sufficient to ‘posterior-ize’ the majority of the embryo, leading to massive apical constriction through expression of the autocrine receptor-ligand pair mist and fog. Ectopic contraction at non-terminal positions requires at least 1 h of high-amplitude Erk signaling, whereas a 30 min pulse of Erk activity patterns non-contractile neurogenic ectoderm during the same time window. In contrast to the canonical ‘transient versus sustained’ model, the cell fate switch is triggered by the cumulative load of Erk signaling, not the duration of a single persistent pulse. Our results reveal that the early fly embryo harbors a classic example of dynamic cell fate control, where the total dose of Erk activity selects between two distinct physiological outcomes.

scholarly journals MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Timothy J Aikin ◽  
Amy F Peterson ◽  
Michael J Pokrass ◽  
Helen R Clark ◽  
Sergi Regot
Keyword(s):  
Large Fraction ◽  
Temporal Patterns ◽  
Genetic Alterations ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Oncogene Expression ◽  
Mapk Activity ◽  
Signaling Dynamics ◽  
Mitogen Activated Protein ◽  
Erk Activity

A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained–but not pulsatile–ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.

scholarly journals FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in ES cells

2015 ◽  
Author(s):  
Christian Schröter ◽  
Pau Rué ◽  
Jonathan P Mackenzie ◽  
Alfonso Martinez Arias
Keyword(s):  
Cell Fate ◽  
Network Architecture ◽  
Cell Model ◽  
Es Cells ◽  
Embryonic Stem ◽  
Transcriptional Regulators ◽  
Mapk Signaling ◽  
Threshold Concentration ◽  
Cell Fates ◽  
Cell Fate Decisions

Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem (ES) cell model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ES cells. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression circuit modulated by FGF/MAPK signaling. This may be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

scholarly journals A Real-Time Biosensor for ERK Activity Reveals Signaling Dynamics during C. elegans Cell Fate Specification

2017 ◽  
Vol 42 (5) ◽  
pp. 542-553.e4 ◽  
Author(s):  
Claire de la Cova ◽  
Robert Townley ◽  
Sergi Regot ◽  
Iva Greenwald
Keyword(s):  
Real Time ◽  
Cell Fate ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
C Elegans ◽  
Signaling Dynamics ◽  
Erk Activity

scholarly journals Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

2017 ◽  
Vol 114 (3) ◽  
pp. E317-E326 ◽  
Author(s):  
Andrew M. Kidger ◽  
Linda K. Rushworth ◽  
Julia Stellzig ◽  
Jane Davidson ◽  
Christopher J. Bryant ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Erk Signaling ◽  
Feedback Mechanisms ◽  
Extracellular Signal Regulated Kinase ◽  
Raf Kinase ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
A Cell ◽  
Erk Activity

Deregulated extracellular signal-regulated kinase (ERK) signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although the MKP DUSP5 both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERK-mediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAFV600E, a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAFV600E-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate.

scholarly journals The presumptive gastric corpus stem cell population is CD44‐positive and expands during metaplasia via increased ERK‐MAPK signaling

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Shradha Khurana ◽  
Won Jae Huh ◽  
Benjamin Moore ◽  
Terrence Riehl ◽  
William F Stenson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Population ◽  
Mapk Signaling ◽  
Stem Cell Population ◽  
Erk Mapk ◽  
Gastric Corpus
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