scholarly journals Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis

2019 ◽  
Author(s):  
Timothy J. Aikin ◽  
Amy F. Peterson ◽  
Michael J. Pokrass ◽  
Helen R. Clark ◽  
Sergi Regot
Keyword(s):  
Cell Fate ◽  
Temporal Patterns ◽  
Mapk Signaling ◽  
Paracrine Signaling ◽  
Cell Behaviors ◽  
Cell Fate Decisions ◽  
Epithelial Tissues ◽  
Mapk Activity ◽  
Signaling Axis ◽  
Quality Control Mechanism

ABSTRACTEpithelial tissues are constantly challenged by individual cell fate decisions while maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their signaling states and cellular behaviors creating competitive interactions that are poorly understood. Here we show that the temporal patterns of MAPK activity are decoded by the ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity coordinates both single and collective cell behaviors to maintain tissue homeostasis.

scholarly journals Nodal signaling regulates endodermal cell motility and actin dynamics via Rac1 and Prex1

2012 ◽  
Vol 198 (5) ◽  
pp. 941-952 ◽  
Author(s):  
Stephanie Woo ◽  
Michael P. Housley ◽  
Orion D. Weiner ◽  
Didier Y.R. Stainier
Keyword(s):  
Cell Fate ◽  
Actin Dynamics ◽  
Migration Behavior ◽  
Nodal Signaling ◽  
Nucleotide Exchange ◽  
Random Motility ◽  
Cell Behaviors ◽  
Cell Fate Decisions ◽  
And Migration ◽  
Endodermal Cells

Embryo morphogenesis is driven by dynamic cell behaviors, including migration, that are coordinated with fate specification and differentiation, but how such coordination is achieved remains poorly understood. During zebrafish gastrulation, endodermal cells sequentially exhibit first random, nonpersistent migration followed by oriented, persistent migration and finally collective migration. Using a novel transgenic line that labels the endodermal actin cytoskeleton, we found that these stage-dependent changes in migratory behavior correlated with changes in actin dynamics. The dynamic actin and random motility exhibited during early gastrulation were dependent on both Nodal and Rac1 signaling. We further identified the Rac-specific guanine nucleotide exchange factor Prex1 as a Nodal target and showed that it mediated Nodal-dependent random motility. Reducing Rac1 activity in endodermal cells caused them to bypass the random migration phase and aberrantly contribute to mesodermal tissues. Together, our results reveal a novel role for Nodal signaling in regulating actin dynamics and migration behavior, which are crucial for endodermal morphogenesis and cell fate decisions.

scholarly journals Graded Mitogen-Activated Protein Kinase Activity Precedes Switch-Like c-Fos Induction in Mammalian Cells

2005 ◽  
Vol 25 (11) ◽  
pp. 4676-4682 ◽  
Author(s):  
Jeffrey P. MacKeigan ◽  
Leon O. Murphy ◽  
Christopher A. Dimitri ◽  
John Blenis
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Oocyte Maturation ◽  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Fate Decisions ◽  
Graded Response ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) pathway is an evolutionarily conserved signaling module that controls important cell fate decisions in a variety of physiological contexts. During Xenopus oocyte maturation, the MAPK cascade converts an increasing progesterone stimulus into a switch-like, all-or-nothing response. While the importance of such switch-like behavior is widely discussed in the literature, it is not known whether the MAPK pathway in mammalian cells exhibits a switch-like or graded response. For this study, we used flow cytometry and immunofluorescence to generate single-cell measurements of MAPK signaling in Swiss 3T3 fibroblasts. In contrast to the case in Xenopus oocytes, we found that ERK activation in individual mammalian cells is not ultrasensitive and shows a graded response to changes in agonist concentration. Thus, the conserved MAPK signaling module exhibits different systems-level properties in different cellular contexts. Furthermore, the graded ERK response was converted into a more switch-like behavior at the level of immediate-early gene induction and cell cycle progression. Thus, while MAPK signaling is involved in all-or-nothing cell fate decisions for both Xenopus oocyte maturation and mammalian fibroblast proliferation, the underlying mechanisms responsible for the switch-like nature of the cellular responses are different in these two systems, with the mechanism appearing to lie downstream of the kinase cascade in mammalian fibroblasts.

scholarly journals Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales

2018 ◽  
Author(s):  
Tanmay Mitra ◽  
Shakti N. Menon ◽  
Sitabhra Sinha
Keyword(s):  
Cell Fate ◽  
Short Term Memory ◽  
Adaptive Dynamics ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Eukaryotic Cells ◽  
Adaptive Responses ◽  
Relaxation Rates ◽  
Cell Fate Decisions ◽  
Mitogen Activated Protein

The mitogen-activated protein kinase (MAPK) signaling cascade, an evolutionarily conserved motif present in all eukaryotic cells, is involved in coordinating critical cell-fate decisions, regulating protein synthesis, and mediating learning and memory. While the steady-state behavior of the pathway stimulated by a time-invariant signal is relatively well-understood, we show using a computational model that it exhibits a rich repertoire of transient adaptive responses to changes in stimuli. When the signal is switched on, the response is characterized by long-lived modulations in frequency as well as amplitude. On withdrawing the stimulus, the activity decays over timescales much longer than that of phosphorylation-dephosphorylation processes, exhibiting reverberations characterized by repeated spiking in the activated MAPK concentration. The long-term persistence of such post-stimulus activity suggests that the cascade retains memory of the signal for a significant duration following its removal, even in the absence of any explicit feedback or cross-talk with other pathways. We find that the molecular mechanism underlying this behavior is related to the existence of distinct relaxation rates for the different cascade components. This results in the imbalance of fluxes between different layers of the cascade, with the repeated reuse of activated kinases as enzymes when they are released from sequestration in complexes leading to one or more spike events following the removal of the stimulus. The persistent adaptive response reported here, indicative of a cellular “short-term” memory, suggests that this ubiquitous signaling pathway plays an even more central role in information processing by eukaryotic cells.

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 A context-dependent bifurcation in the Pointed transcriptional effector network contributes specificity and robustness to retinal cell fate acquisition

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009216
Author(s):  
Chudong Wu ◽  
Jean-François Boisclair Lachance ◽  
Michael Z. Ludwig ◽  
Ilaria Rebay
Keyword(s):  
Cell Fate ◽  
Expression Patterns ◽  
Transcriptional Response ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Null Alleles ◽  
Retinal Cell ◽  
Intrinsic Activity ◽  
Fate Specification ◽  
Mapk Activity

Spatiotemporally precise and robust cell fate transitions, which depend on specific signaling cues, are fundamental to the development of appropriately patterned tissues. The fidelity and precision with which photoreceptor fates are recruited in the Drosophila eye exemplifies these principles. The fly eye consists of a highly ordered array of ~750 ommatidia, each of which contains eight distinct photoreceptors, R1-R8, specified sequentially in a precise spatial pattern. Recruitment of R1-R7 fates requires reiterative receptor tyrosine kinase / mitogen activated protein kinase (MAPK) signaling mediated by the transcriptional effector Pointed (Pnt). However the overall signaling levels experienced by R2-R5 cells are distinct from those experienced by R1, R6 and R7. A relay mechanism between two Pnt isoforms initiated by MAPK activation directs the universal transcriptional response. Here we ask how the generic Pnt response is tailored to these two rounds of photoreceptor fate transitions. We find that during R2-R5 specification PntP2 is coexpressed with a closely related but previously uncharacterized isoform, PntP3. Using CRISPR/Cas9-generated isoform specific null alleles we show that under otherwise wild type conditions, R2-R5 fate specification is robust to loss of either PntP2 or PntP3, and that the two activate pntP1 redundantly; however under conditions of reduced MAPK activity, both are required. Mechanistically, our data suggest that intrinsic activity differences between PntP2 and PntP3, combined with positive and unexpected negative transcriptional auto- and cross-regulation, buffer first-round fates against conditions of compromised RTK signaling. In contrast, in a mechanism that may be adaptive to the stronger signaling environment used to specify R1, R6 and R7 fates, the Pnt network resets to a simpler topology in which PntP2 uniquely activates pntP1 and auto-activates its own transcription. We propose that differences in expression patterns, transcriptional activities and regulatory interactions between Pnt isoforms together facilitate context-appropriate cell fate specification in different signaling environments.

scholarly journals Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine

2014 ◽  
Vol 111 (9) ◽  
pp. 3472-3477 ◽  
Author(s):  
Julian Heuberger ◽  
Frauke Kosel ◽  
Jingjing Qi ◽  
Katja S. Grossmann ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
Cell Fate ◽  
Paneth Cell ◽  
Mapk Signaling ◽  
Cell Fate Decisions

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 FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells

Development ◽  
2015 ◽  
Vol 142 (24) ◽  
pp. 4205-4216 ◽  
Author(s):  
C. Schro ter ◽  
P. Rue ◽  
J. P. Mackenzie ◽  
A. Martinez Arias
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Cell Fate Decisions ◽  
Switching Threshold

scholarly journals Pulsatile MAPK Signaling Modulates p53 Activity to Control Cell Fate Decisions at the G2 Checkpoint for DNA Damage

Cell Reports ◽  
2020 ◽  
Vol 30 (7) ◽  
pp. 2083-2093.e5 ◽  
Author(s):  
Siddharth De ◽  
Callum Campbell ◽  
Ashok R. Venkitaraman ◽  
Alessandro Esposito
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Control Cell ◽  
Mapk Signaling ◽  
Cell Fate Decisions ◽  
G2 Checkpoint

scholarly journals The hypoxia-response pathway modulates RAS/MAPK–mediated cell fate decisions in Caenorhabditis elegans

2019 ◽  
Vol 2 (3) ◽  
pp. e201800255 ◽  
Author(s):  
Sabrina Maxeiner ◽  
Judith Grolleman ◽  
Tobias Schmid ◽  
Jan Kammenga ◽  
Alex Hajnal
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Oxygen Concentration ◽  
Mapk Pathway ◽  
Atmospheric Oxygen ◽  
Mapk Signaling ◽  
Nuclear Hormone Receptor ◽  
Induced Differentiation ◽  
Hypoxia Response ◽  
Cell Fate Decisions

Animals need to adjust many cellular functions to oxygen availability to adapt to changing environmental conditions. We have used the nematode Caenorhabditis elegans as a model to investigate how variations in oxygen concentrations affect cell fate specification during development. Here, we show that several processes controlled by the conserved RTK/RAS/MAPK pathway are sensitive to changes in the atmospheric oxygen concentration. In the vulval precursor cells (VPCs), the hypoxia-inducible factor HIF-1 activates the expression of the nuclear hormone receptor NHR-57 to counteract RAS/MAPK–induced differentiation. Furthermore, cross-talk between the NOTCH and hypoxia-response pathways modulates the capability of the VPCs to respond to RAS/MAPK signaling. Lateral NOTCH signaling positively regulates the prolyl hydroxylase EGL-9, which promotes HIF-1 degradation in uncommitted VPCs and permits RAS/MAPK–induced differentiation. By inducing DELTA family NOTCH ligands, RAS/MAPK signaling creates a positive feedback loop that represses HIF-1 and NHR-57 expression in the proximal VPCs and keeps them capable of differentiating. This regulatory network formed by the NOTCH, hypoxia, and RAS/MAPK pathways may allow the animals to adapt developmental processes to variations in oxygen concentration.

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