scholarly journals Central Roles and Regulatory Mechanisms of Dual-Specificity MAPK Phosphatases in Developmental and Stress Signaling

2018 ◽  
Vol 9 ◽  
Author(s):  
Lingyan Jiang ◽  
Yinhua Chen ◽  
Lijuan Luo ◽  
Scott C. Peck
Keyword(s):  
Regulatory Mechanisms ◽  
Stress Signaling ◽  
Dual Specificity ◽  
Mapk Phosphatases

scholarly journals Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation

2019 ◽  
Vol 20 (5) ◽  
pp. 1170 ◽  
Author(s):  
Caroline Nunes-Xavier ◽  
Laura Zaldumbide ◽  
Olaia Aurtenetxe ◽  
Ricardo López-Almaraz ◽  
José López ◽  
...  
Keyword(s):  
Cell Growth ◽  
Map Kinases ◽  
Current Knowledge ◽  
Neuroblastoma Cell ◽  
Neuronal Cell ◽  
Predictive Biomarkers ◽  
Dual Specificity ◽  
Mapk Phosphatases ◽  
Cell Growth And Differentiation ◽  
Dual Specificity Phosphatases

Dual-specificity phosphatases (DUSPs) are important regulators of neuronal cell growth and differentiation by targeting proteins essential to neuronal survival in signaling pathways, among which the MAP kinases (MAPKs) stand out. DUSPs include the MAPK phosphatases (MKPs), a family of enzymes that directly dephosphorylate MAPKs, as well as the small-size atypical DUSPs, a group of low molecular-weight enzymes which display more heterogeneous substrate specificity. Neuroblastoma (NB) is a malignancy intimately associated with the course of neuronal and neuroendocrine cell differentiation, and constitutes the source of more common extracranial solid pediatric tumors. Here, we review the current knowledge on the involvement of MKPs and small-size atypical DUSPs in NB cell growth and differentiation, and discuss the potential of DUSPs as predictive biomarkers and therapeutic targets in human NB.

scholarly journals Bidirectional regulation of glial potassium buffering – glioprotection versus neuroprotection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hailun Li ◽  
Lorenzo Lones ◽  
Aaron DiAntonio
Keyword(s):  
Therapeutic Strategy ◽  
Neuronal Excitability ◽  
Therapeutic Potential ◽  
Regulatory Mechanisms ◽  
Stress Signaling ◽  
Bidirectional Regulation ◽  
Regulated Gene Expression ◽  
Potassium Buffering ◽  
Expression Program ◽  
G Protein Coupled

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A salt inducible kinase 3 (SIK3)-regulated gene expression program controls the glial capacity to buffer K+ and water in Drosophila, however upstream regulatory mechanisms are unknown. Here, we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic G-protein-coupled receptor (GPCR) OctβR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway is inactivated. Reactivation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened life span in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.

scholarly journals Dual specificity phosphatases 10 and 16 are positive regulators of EGF-stimulated ERK activity: Indirect regulation of ERK signals by JNK/p38 selective MAPK phosphatases

2012 ◽  
Vol 24 (5) ◽  
pp. 1002-1011 ◽  
Author(s):  
Ann R. Finch ◽  
Christopher J. Caunt ◽  
Rebecca M. Perrett ◽  
Krasimira Tsaneva-Atanasova ◽  
Craig A. McArdle
Keyword(s):  
Dual Specificity ◽  
Positive Regulators ◽  
Mapk Phosphatases ◽  
Dual Specificity Phosphatases ◽  
Erk Activity

scholarly journals Gonadotropin-Releasing Hormone and Protein Kinase C Signaling to ERK: Spatiotemporal Regulation of ERK by Docking Domains and Dual-Specificity Phosphatases

2009 ◽  
Vol 23 (4) ◽  
pp. 510-519 ◽  
Author(s):  
Stephen Paul Armstrong ◽  
Christopher James Caunt ◽  
Craig Alexander McArdle
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Ester ◽  
Fluorescent Protein ◽  
Erk Activation ◽  
Kinase C ◽  
Dual Specificity ◽  
Mapk Phosphatases ◽  
Dual Specificity Phosphatases ◽  
Green Fluorescent

Abstract Activated ERK translocates to the nucleus to regulate transcription. Spatiotemporal aspects of this response dictate biological consequences and are influenced by dual-specificity phosphatases (DUSPs) that can scaffold and dephosphorylate ERK. In HeLa cells, GnRH causes transient and protein kinase C (PKC)-dependent ERK activation, but termination mechanisms are unknown. We now explore DUSP roles using short inhibitory RNA to knock down endogenous ERK, adenoviruses to express GnRH receptors and add-back ERK2-GFP, and automated microscopy to monitor ERK location and activation. GnRH caused rapid and transient increases in dual phosphorylated ERK2 (ppERK2) and nuclear to cytoplasmic ERK2-green fluorescent protein (GFP) ratio, whereas responses to a PKC-activating phorbol ester were more sustained. In cells expressing D319N ERK2-GFP (D319N mutation impairs docking-domain-dependent binding to DUSPs), GnRH caused more sustained increases in ppERK2 and nuclear to cytoplasmic ERK2-GFP ratio and also had more pronounced effects on Egr-1 luciferase (a transcriptional reporter for ERK activation). Cycloheximide caused more sustained effects of GnRH and phorbol ester on ppERK, suggesting termination by nuclear-inducible DUSPs. GnRH also increased expression of nuclear-inducible DUSP1 and -4, but their knockdown did not alter GnRH-mediated ERK signaling. Screening a short inhibitory RNA library targeting 16 DUSPs (nuclear-inducible DUSPs, cytoplasmic ERK MAPK phosphatases, c-Jun N-terminal kinase/p38 MAPK phosphatases, and atypical DUSPs) revealed GnRH effects to be influenced by DUSPs 5, 9, 10, 16, and 3 (i.e. by each DUSP class). Thus, GnRH-mediated ERK responses (like PKC-mediated ERK responses) are dependent on protein neosynthesis and docking-domain-dependent binding, but for GnRH activation (unlike PKC activation), this does not reflect dependence on nuclear-inducible DUSPs. Termination of these GnRH effects is apparently dependent upon a preexisting rapid turnover protein.

scholarly journals Unbiased proteomic mapping of the LINE-1 promoter using CRISPR Cas9

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Erica M. Briggs ◽  
Paolo Mita ◽  
Xiaoji Sun ◽  
Susan Ha ◽  
Nikita Vasilyev ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Protein Phosphatase ◽  
Transcriptional Regulators ◽  
Regulatory Mechanisms ◽  
Regulatory Sequence ◽  
Dual Specificity ◽  
Copy And Paste ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein ◽  
Long Interspersed Element

Abstract Background The autonomous retroelement Long Interspersed Element-1 (LINE-1) mobilizes though a copy and paste mechanism using an RNA intermediate (retrotransposition). Throughout human evolution, around 500,000 LINE-1 sequences have accumulated in the genome. Most of these sequences belong to ancestral LINE-1 subfamilies, including L1PA2-L1PA7, and can no longer mobilize. Only a small fraction of LINE-1 sequences, approximately 80 to 100 copies belonging to the L1Hs subfamily, are complete and still capable of retrotransposition. While silenced in most cells, many questions remain regarding LINE-1 dysregulation in cancer cells. Results Here, we optimized CRISPR Cas9 gRNAs to specifically target the regulatory sequence of the L1Hs 5’UTR promoter. We identified three gRNAs that were more specific to L1Hs, with limited binding to older LINE-1 sequences (L1PA2-L1PA7). We also adapted the C-BERST method (dCas9-APEX2 Biotinylation at genomic Elements by Restricted Spatial Tagging) to identify LINE-1 transcriptional regulators in cancer cells. Our LINE-1 C-BERST screen revealed both known and novel LINE-1 transcriptional regulators, including CTCF, YY1 and DUSP1. Conclusion Our optimization and evaluation of gRNA specificity and application of the C-BERST method creates a tool for studying the regulatory mechanisms of LINE-1 in cancer. Further, we identified the dual specificity protein phosphatase, DUSP1, as a novel regulator of LINE-1 transcription.

scholarly journals Bidirectional regulation of glial potassium buffering: glioprotection versus neuroprotection

2020 ◽  
Author(s):  
Hailun Li ◽  
Lorenzo Lones ◽  
Aaron DiAntonio
Keyword(s):  
Therapeutic Strategy ◽  
Neuronal Excitability ◽  
Therapeutic Potential ◽  
Buffering Capacity ◽  
Regulatory Mechanisms ◽  
Stress Signaling ◽  
Bidirectional Regulation ◽  
Regulated Gene Expression ◽  
Potassium Buffering ◽  
Expression Program

ABSTRACTGlia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A SIK3-regulated gene expression program controls the glial capacity to buffer K+ and water, however upstream regulatory mechanisms are unknown. Here we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic GPCR OctβR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway in inactivated. Re-activation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened lifespan in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.

scholarly journals Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast

2013 ◽  
Vol 211 (1) ◽  
pp. 153-163 ◽  
Author(s):  
Jun Hirose ◽  
Hironari Masuda ◽  
Naoto Tokuyama ◽  
Yasunori Omata ◽  
Takumi Matsumoto ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Conditional Knockout ◽  
Conditional Deletion ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Receptor Activator ◽  
Mitogen Activated Protein ◽  
Mapk Phosphatases

Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal–related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.

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