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 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 GP78 Cooperates with Dual-Specificity Phosphatase 1 To Stimulate Epidermal Growth Factor Receptor-Mediated Extracellular Signal-Regulated Kinase Signaling

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Dhong Hyo Kho ◽  
Mohammed Hafiz Uddin ◽  
Madhumita Chatterjee ◽  
Andreas Vogt ◽  
Avraham Raz ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Epidermal Growth ◽  
Proliferation And Invasion

ABSTRACT GP78 is an autocrine motility factor (AMF) receptor (AMFR) with E3 ubiquitin ligase activity that plays a significant role in tumor cell proliferation, motility, and metastasis. Aberrant extracellular signal-regulated kinase (ERK) activation via receptor tyrosine kinases promotes tumor proliferation and invasion. The activation of GP78 leads to ERK activation, but its underlying mechanism is not fully understood. Here, we show that GP78 is required for epidermal growth factor receptor (EGFR)-mediated ERK activation. On one hand, GP78 interacts with and promotes the ubiquitination and subsequent degradation of dual-specificity phosphatase 1 (DUSP1), an endogenous negative regulator of mitogen-activated protein kinases (MAPKs), resulting in ERK activation. On the other hand, GP78 maintains the activation status of EGFR, as evidenced by the fact that EGF fails to induce EGFR phosphorylation in GP78-deficient cells. By the regulation of both EGFR and ERK activation, GP78 promotes cell proliferation, motility, and invasion. Therefore, this study identifies a previously unknown signaling pathway by which GP78 stimulates ERK activation via DUSP1 degradation to mediate EGFR-dependent cancer cell proliferation and invasion.

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 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.

Downregulation of Sulfiredoxin (Srx) Suppressed Cell Proliferation Migration and Invasion Through Inhibiting Extracellular Signal-Regulated Kinase/Nrf2 Pathway in Hepatocellular Carcinoma

2021 ◽  
Vol 11 (11) ◽  
pp. 2137-2145
Author(s):  
Xuejuan Zhu ◽  
Danqian Lu
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Colony Formation ◽  
Migration And Invasion ◽  
Related Factor ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Nrf2 Signaling Pathway

Background: Sulfiredoxin (Srx) has been identified to play important roles in the development of various cancers. However, the precise effects and underlying mechanism of Srx on the progression of HCC are far from being fully understood. Materials and Methods: The abundances of Srx in THLE-2 cell and HCC cell lines were determined by western blot and RT-qPCR. Next, SK-Hep-1 cells were transfected with shRNA-Srx or shRNA-NC and treated with TBHQ (an extracellular signal-regulated kinase (ERK) activator) for functional experiments. Then, CCK8 and colony formation assays were used to determine cell proliferation and clone-forming abilities in vitro. Cell migration and invasion were assessed via wound healing and transwell assays. The expression of MMP2, MMP9 and key members in ERK/nuclear factor E2 related factor (Nrf2) signaling pathway was detected by performing western blot analysis. Results: We reported evidence that Srx was frequently up-regulated in HCC cell lines. Srx interference constrained cell proliferation, colony formation rate, migration and invasion of SK-Hep-1 cells. Moreover, mechanistic investigations indicated that Srx interference significantly inhibited the activation of ERK/Nrf2 signaling pathway, and ERK activator TBHQ can reverse the functions of Srx interference in SK-Hep-1 cells. Conclusion: Overall, Downregulation of Srx might impede HCC progression by suppressing ERK/Nrf2 signaling pathway. Findings in the current study reported the functional involvement and molecular mechanism of Srx in HCC, suggesting that Srx might have a potential therapeutic value in HCC treatment.

Sign in / Sign up

Export Citation Format

Share Document