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 Wnt-dependent activation of ERK mediates repression of chondrocyte fate during calvarial development

2021 ◽  
Author(s):  
Beatriz Ibarra ◽  
Cody Machen ◽  
Radhika P. Atit
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Erk Signaling ◽  
Cranial Bone ◽  
Erk Activation ◽  
Cell Fate Decisions ◽  
Extracellular Signal ◽  
Dependent Cell ◽  
Calvarial Osteoblast

AbstractWnt signaling regulates cell fate decisions in diverse contexts during development, and loss of Wnt signaling in the cranial mesenchyme results in a robust and binary cell fate switch from cranial bone to ectopic cartilage. The Extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and Wnt signaling pathways are activated during calvarial osteoblast cell fate selection. Here, we test the hypothesis that ERK signaling is a mediator of Wnt-dependent cell fate decisions in the cranial mesenchyme. First, we show that loss ofErk1/2 in the cranial mesenchyme results in a diminished domain of osteoblast marker expression and increased expression of cartilage fate markers and ectopic cartilage formation in the frontal bone primordia. Second, we show that mesenchyme Wnt/β-catenin signaling andWntlessare required for ERK activation in calvarial osteoblasts. Third, we demonstrate that Wnt and ERK signaling pathways function together to repress Sox9 expression in mouse cranial mesenchyme. Our results demonstrate a link between the Wnt and ERK signaling pathways in regulating lineage selection in a subset of calvarial cells and provide new insights into Wnt-dependent cell fate decisions.

scholarly journals Wnt-Dependent Activation of ERK Mediates Repression of Chondrocyte Fate during Calvarial Development

2021 ◽  
Vol 9 (3) ◽  
pp. 23
Author(s):  
Beatriz A Ibarra ◽  
Cody Machen ◽  
Radhika P. Atit
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Erk Signaling ◽  
Cranial Bone ◽  
Erk Activation ◽  
Cell Fate Decisions ◽  
Extracellular Signal ◽  
Dependent Cell ◽  
Calvarial Osteoblast

Wnt signaling regulates cell fate decisions in diverse contexts during development, and loss of Wnt signaling in the cranial mesenchyme results in a robust and binary cell fate switch from cranial bone to ectopic cartilage. The Extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and Wnt signaling pathways are activated during calvarial osteoblast cell fate selection. Here, we test the hypothesis that ERK signaling is a mediator of Wnt-dependent cell fate decisions in the cranial mesenchyme. First, we show that loss of Erk1/2 in the cranial mesenchyme results in a diminished domain of osteoblast marker expression and increased expression of cartilage fate markers and ectopic cartilage formation in the frontal bone primordia. Second, we show that mesenchyme Wnt/β-catenin signaling and Wntless are required for ERK activation in calvarial osteoblasts. Third, we demonstrate that Wnt and ERK signaling pathways function together to repress SOX9 expression in mouse cranial mesenchyme. Our results demonstrate an interaction between the Wnt and ERK signaling pathways in regulating lineage selection in a subset of calvarial cells and provide new insights into Wnt-dependent cell fate decisions.

scholarly journals Inhibition of gonadotropin-stimulated steroidogenesis by the erk cascade

2019 ◽  
Author(s):  
Rony Seger ◽  
Tamar Hanoch ◽  
Revital Rosenberg ◽  
Ada Dantes ◽  
Wolfgang E. Merz ◽  
...  
Keyword(s):  
Protein A ◽  
Erk Signaling ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Progesterone Production ◽  
Extracellular Signal ◽  
Progesterone Synthesis ◽  
Steroidogenic Acute Regulatory ◽  
Erk Activity ◽  
Stimulation Of

LH and FSH are two important hormones in the regulation of granulosa cells. Their effects are mediated mainly by cAMP/PKA signaling, bit the activity of the extracellular signal-regulated kinase (ERK) signaling cascade is elevated as well. We studied the involvement of the ERK cascade in LH and FSH-induced steroidogenesis in two granulosa-derived cell lines, rLHR-4 and rFSHR-17, respectively. We found that stimulation of these cells with the appropriate gonadotropin induced ERK activation as well as progesterone production, downstream of PKA. Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production, which was correlated with increased-expression of the steroidogenic acute regulatory (StAR) protein, a key regulator of progesterone synthesis. Therefore, it is likely that gonadotropin-stimulated progesterone formation is regulated by a pathway that includes PKA and StAR, and this process is downregulated by ERK, due to attenuation of StAR expression. Our results suggest that activation of PKA signaling by gonadotropins not only induces steroidogenesis, but also activates downregulation machinery involving the ERK cascade. The activation of ERK by gonadotropins as well as by other agents, may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis.

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.

Role of extracellular signal-regulated kinase (ERK) signaling in nucleotide excision repair and genotoxicity in response to As(III) and Pb(II)

2008 ◽  
Vol 80 (12) ◽  
pp. 2735-2750
Author(s):  
Ju-Pi Li ◽  
Chun-Yu Wang ◽  
Yen-An Tang ◽  
Yun-Wei Lin ◽  
Jia-Ling Yang
Keyword(s):  
Signaling Pathways ◽  
Nucleotide Excision Repair ◽  
Mammalian Cells ◽  
Excision Repair ◽  
Erk Signaling ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Nucleotide Excision

Arsenic and lead can induce genetic injuries and epigenetic signaling pathways in cultured mammalian cells. To test whether signaling pathways affect the extent of genetic injuries, we explored the impacts of extracellular signal-regulated kinase 1 and 2 (ERK) on nucleotide excision repair (NER), cytotoxicity, and genotoxicity following sodium arsenite [As(III)] and lead acetate [Pb(II)]. Sustained ERK activation was observed in human cells exposed to As(III) and Pb(II). As(III) inhibited the cellular NER synthesis capability; conversely, Pb(II) stimulated it. ERK activation contributed to the As(III)-induced NER inhibition and micronucleus formation. In contrast, this signal was required for inducing cellular NER activity and preventing mutagenesis following Pb(II). ERK activation by Pb(II) was dependent on protein kinase C (PKCα) that also exhibited anti-mutagenicity. Enforced expression of ERK signaling markedly elevated the cellular NER activity, which was suppressed by As(III). Nonetheless, ERK activation could counteract the cytotoxicity caused by these two metals. Together, the results indicate that pro-survival ERK signaling exhibits dual and opposing impacts on NER process following As(III) and Pb(II) exposures. The findings also suggest that ERK is an important epigenetic signaling in the determination of metal genotoxicity.

scholarly journals Role of Phosphoinositide 3-Kinase and Endocytosis in Nerve Growth Factor-Induced Extracellular Signal-Regulated Kinase Activation via Ras and Rap1

2000 ◽  
Vol 20 (21) ◽  
pp. 8069-8083 ◽  
Author(s):  
Randall D. York ◽  
Derek C. Molliver ◽  
Savraj S. Grewal ◽  
Paula E. Stenberg ◽  
Edwin W. McCleskey ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Map Kinase ◽  
Pc12 Cells ◽  
Erk Signaling ◽  
Nerve Growth ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Phosphoinositide 3 Kinase

ABSTRACT Neurotrophins promote multiple actions on neuronal cells including cell survival and differentiation. The best-studied neurotrophin, nerve growth factor (NGF), is a major survival factor in sympathetic and sensory neurons and promotes differentiation in a well-studied model system, PC12 cells. To mediate these actions, NGF binds to the TrkA receptor to trigger intracellular signaling cascades. Two kinases whose activities mediate these processes include the mitogen-activated protein (MAP) kinase (or extracellular signal-regulated kinase [ERK]) and phosphoinositide 3-kinase (PI3-K). To examine potential interactions between the ERK and PI3-K pathways, we studied the requirement of PI3-K for NGF activation of the ERK signaling cascade in dorsal root ganglion cells and PC12 cells. We show that PI3-K is required for TrkA internalization and participates in NGF signaling to ERKs via distinct actions on the small G proteins Ras and Rap1. In PC12 cells, NGF activates Ras and Rap1 to elicit the rapid and sustained activation of ERKs respectively. We show here that Rap1 activation requires both TrkA internalization and PI3-K, whereas Ras activation requires neither TrkA internalization nor PI3-K. Both inhibitors of PI3-K and inhibitors of endocytosis prevent GTP loading of Rap1 and block sustained ERK activation by NGF. PI3-K and endocytosis may also regulate ERK signaling at a second site downstream of Ras, since both rapid ERK activation and the Ras-dependent activation of the MAP kinase kinase kinase B-Raf are blocked by inhibition of either PI3-K or endocytosis. The results of this study suggest that PI3-K may be required for the signals initiated by TrkA internalization and demonstrate that specific endocytic events may distinguish ERK signaling via Rap1 and Ras.

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 Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6) Stimulates Extracellular Signal–regulated Kinase (ERK) Activity in CD40 Signaling Along a Ras-independent Pathway

1998 ◽  
Vol 187 (2) ◽  
pp. 237-244 ◽  
Author(s):  
Masaki Kashiwada ◽  
Yumiko Shirakata ◽  
Jun-Ichiro Inoue ◽  
Hiroyasu Nakano ◽  
Kenji Okazaki ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Deletion Mutant ◽  
Tumor Necrosis Factor Receptor ◽  
Dominant Negative ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Erk Activity ◽  
Necrosis Factor

CD40 activates nuclear factor kappa B (NFκB) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal–regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor–associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NFκB activation. Here we report that transient expression of TRAF6 stimulated both ERK and NFκB activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40Δ246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40Δ246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40Δ246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.

Extracellular signal-regulated kinase pathway is differentially involved in β-agonist-induced hypertrophy in slow and fast muscles

2007 ◽  
Vol 292 (5) ◽  
pp. C1681-C1689 ◽  
Author(s):  
H. Shi ◽  
C. Zeng ◽  
A. Ricome ◽  
K. M. Hannon ◽  
A. L. Grant ◽  
...  
Keyword(s):  
Fiber Type ◽  
Erk Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Slow Twitch ◽  
Fast Twitch ◽  
Erk Activity ◽  
Fast Muscles ◽  
Slow And Fast Muscles

The molecular mechanisms controlling β-adrenergic receptor agonist (BA)-induced skeletal muscle hypertrophy are not well known. We presently report that BA exerts a distinct muscle- and muscle fiber type-specific hypertrophy. Moreover, we have shown that pharmacologically or genetically attenuating extracellular signal-regulated kinase (ERK) signaling in muscle fibers resulted in decreases ( P < 0.05) in fast but not slow fiber type-specific reporter gene expressions in response to BA exposure in vitro and in vivo. Consistent with these data, forced expression of MAPK phosphatase 1, a nuclear protein that dephosphorylates ERK1/2, in fast-twitch skeletal muscle ablated ( P < 0.05) the hypertrophic effects of BA feeding (clenbuterol, 20 parts per million in water) in vivo. Further analysis has shown that BA-induced phosphorylation and activation of ERK occurred to a greater ( P < 0.05) extent in fast myofibers than in slow myofibers. Analysis of the basal level of ERK activity in slow and fast muscles revealed that ERK1/2 is activated to a greater extent in fast- than in slow-twitch muscles. These data indicate that ERK signaling is differentially involved in BA-induced hypertrophy in slow and fast skeletal muscles, suggesting that the increased abundance of phospho-ERK1/2 and ERK activity found in fast-twitch myofibers, compared with their slow-twitch counterparts, may account, at least in part, for the fiber type-specific hypertrophy induced by BA stimulation. These data suggest that fast myofibers are pivotal in the adaptation of muscle to environmental cues and that the mechanism underlying this change is partially mediated by the MAPK signaling cascade.

scholarly journals Intercellular propagation of extracellular signal-regulated kinase activation revealed by in vivo imaging of mouse skin

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Toru Hiratsuka ◽  
Yoshihisa Fujita ◽  
Honda Naoki ◽  
Kazuhiro Aoki ◽  
Yuji Kamioka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mouse Skin ◽  
Egf Receptors ◽  
M Cell ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Erk Activity

Extracellular signal-regulated kinase (ERK) is a key effector of many growth signalling pathways. In this study, we visualise epidermal ERK activity in living mice using an ERK FRET biosensor. Under steady-state conditions, the epidermis occasionally revealed bursts of ERK activation patterns where ERK activity radially propagated from cell to cell. The frequency of this spatial propagation of radial ERK activity distribution (SPREAD) correlated with the rate of epidermal cell division. SPREADs and proliferation were stimulated by 12-O-tetradecanoylphorbol 13-acetate (TPA) in a manner dependent on EGF receptors and their cognate ligands. At the wounded skin, ERK activation propagated as trigger wave in parallel to the wound edge, suggesting that ERK activation propagation can be superimposed. Furthermore, by visualising the cell cycle, we found that SPREADs were associated with G2/M cell cycle progression. Our results provide new insights into how cell proliferation and transient ERK activity are synchronised in a living tissue.

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