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 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.

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 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 Stimulation of extracellular signal-regulated kinase by pituitary adenylate cyclase-activating polypeptide in alpha T3-1 gonadotrophs

2001 ◽  
Vol 171 (3) ◽  
pp. R5-10 ◽  
Author(s):  
RC Fowkes ◽  
J Burch ◽  
JM Burrin
Keyword(s):  
Adenylate Cyclase ◽  
Mapk Pathway ◽  
Luciferase Reporter ◽  
Glycoprotein Hormone ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Pituitary Adenylate Cyclase ◽  
Pre Treatment ◽  
Stimulation Of

The putative hypophysiotropic factor pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates glycoprotein hormone alpha-subunit (alpha GSU) gene transcription and secretion in the clonal gonadotroph alpha T3-1 cell line. The specific signalling pathways regulating these actions of PACAP have not been clearly defined. We have examined the possibility that mitogen activated protein kinases (MAPKs) may play a role in mediating the effects of PACAP on alpha T3-1 gonadotrophs. Treatment of alpha T3-1 cells with PACAP (100 nM) or epidermal growth factor (EGF, 10 nM) for 5 min significantly stimulated extracellular signal-regulated kinase activity (ERK, a component of the MAPK pathway) as determined by an immunocomplex assay. Pre-treatment of alpha T3-1 cells with the specific MAPK kinase (MEK) inhibitor, U0126, blocked PACAP and EGF-induced activation of ERK. Transcriptional stimulation of a human alpha GSU-luciferase reporter construct by PACAP was unaffected by U0126 treatment. However, pre-treatment with U0126 significantly inhibited PACAP stimulation of [(3)H]-thymidine incorporation in alpha T3-1 cells. Thus our results suggest that PACAP stimulates ERK activation in alpha T3-1 cells, and that the functional effect of this ERK activation is increased DNA synthesis and cell proliferation rather then transcriptional activation of the alpha GSU gene.

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.

Ribosomal S6 kinase-1 modulates interleukin-1β-induced persistent activation of NF-κB through phosphorylation of IκBβ

2006 ◽  
Vol 291 (6) ◽  
pp. C1336-C1345 ◽  
Author(s):  
Shanqin Xu ◽  
Hossein Bayat ◽  
Xiuyun Hou ◽  
Bingbing Jiang
Keyword(s):  
Nuclear Translocation ◽  
Erk Signaling ◽  
Signaling Cascade ◽  
S6 Kinase ◽  
Small Interference Rna ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Ribosomal S6 Kinase

Activation of NF-κB requires the phosphorylation and degradation of its associated inhibitory proteins, IκB. Previously, we reported that the extracellular signal-regulated kinase (ERK) is required for IL-1β to induce persistent activation of NF-κB in cultured rat vascular smooth muscle cells (VSMCs). The present study examined the mechanism by which the ERK signaling cascade modulates the duration of NF-κB activation. In cultured rat VSMCs, IL-1β activated ERK and induced degradation of both IκBα and IκBβ, which was associated with nuclear translocation of both ribosomal S6 kinase (RSK)1 and NF-κB p65. RSK1, a downstream kinase of ERK, was associated with an IκBβ/NF-κB complex, which was independent of the phosphorylation status of RSK1. Treatment of VSMCs with IL-1β decreased IκBβ in the RSK1/IκBβ/NF-κB complex, an effect that was attenuated by inhibition of ERK activation. Knockdown of RSK1 by small interference RNA attenuated the IL-1β-induced IκBβ decrease without influencing ether ERK phosphorylation or the earlier IκBα degradation. By using recombinant wild-type and mutant IκBβ proteins, both active ERK2 and RSK1 were found to directly phosphorylate IκBβ, but only active RSK1 phosphorylated IκBβ on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation. In conclusion, in the ERK signaling cascade, RSK1 is a key component that directly phosphorylates IκBβ and contributes to the persistent activation of NF-κB by IL-1β.

scholarly journals Extracellular Signal-Regulated Kinase Mediates Stimulation of TGF-β1 and Matrix by High Glucose in Mesangial Cells

2000 ◽  
Vol 11 (12) ◽  
pp. 2222-2230
Author(s):  
MOTOHIDE ISONO ◽  
M. CARMEN IGLESIAS-DE LA CRUZ ◽  
SHELDON CHEN ◽  
SOON WON HONG ◽  
FUAD N. ZIYADEH
Keyword(s):  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Specific Inhibitor ◽  
Mrna Levels ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Tgf Β1 ◽  
Stimulation Of

Abstract. High ambient glucose exerts its injurious effects on renal cells through nonenzymatic and enzymatic pathways, including altered signal transduction and upregulation of the transforming growth factor-β (TGF-β) system. Extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) cascade, is activated in mesangial cells cultured in high glucose and in glomeruli of diabetic rats. However, the biologic consequences of ERK activation in the kidney have not been investigated. To clarify the role of ERK activation, mouse mesangial cells were exposed to normal (5.5 mM) or high (25 mM) glucose with or without addition of PD98059, a specific inhibitor of MAPK/ERK kinase (MEK), an upstream kinase activator of ERK. Cells that were exposed to high glucose exhibited significant increases in ERK activity, TGF-β1 expression (total protein, mRNA levels, and promoter activity), [3H]-proline uptake, and α1(I) collagen and fibronectin mRNA levels. Treatment with PD98059 (up to 25 μM) significantly inhibited these parameters. In contrast, 25 μM PD98059 had no significant effect on any of the parameters measured in cells that were exposed to normal glucose. Overexpression of MAPK phosphatase CL 100 prevented TGF-β1 promoter activation by high glucose, confirming the involvement of the MEK-ERK pathway in response to high glucose. The conclusion is that activation of ERK in mesangial cells is responsible for high-glucose-induced stimulation of TGF-β1 and contributes to the increased extracellular matrix expression.

scholarly journals Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells

2000 ◽  
Vol 352 (3) ◽  
pp. 701-708 ◽  
Author(s):  
Samia REFFAS ◽  
Werner SCHLEGEL
Keyword(s):  
Protein Kinases ◽  
Embryonic Stem Cell Line ◽  
Embryonic Stem ◽  
Cell Fractionation ◽  
Mitogen Activated Protein Kinases ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Activity

Activation of mitogen-activated protein kinases (MAPKs), their upstream activators MAPK kinases (MAPKKs or MEKs) and induction of MKP-1 (CL100/3CH134) and MKP-3 (Pyst1/rVH6) dual-specificity MAPK phosphatases (MKPs) were studied in the mouse embryonic stem cell line P19 during the 7 day induction of neuronal differentiation triggered by aggregation and retinoic acid. ERK (extracellular signal-regulated kinase), but not JNK (c-Jun N-terminal kinase), was found activated with biphasic kinetics: a first transient phase on days 1 and 2, followed by a second activation that was sustained until the appearance of a neuronal phenotype. MEK activation appeared coincident with ERK activation. Cytosolic MKP-3 was induced in parallel to ERK activation, the induction being dependent on ERK activation, as was shown using the MEK-1 inhibitor PD98059. In contrast, nuclear MKP-1 was transiently elevated at 48h, coincident with ERK inactivation and independently of ERK activity. As shown by cell fractionation, activated ERK is translocated to the nucleus. The complementary induction of ERK-specific phosphatases MKP-1 and MKP-3 permits precise and independent control of cytoplasmic and nuclear ERK activity, most probably required to properly induce a complex cellular programme of differentiation.

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