Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases

Bhore, Noopur; Wang, Bo-Jeng; Chen, Yun-Wen; Liao, Yung‐Feng

doi:10.3390/ijms18091963

Cited by 25 publications

(20 citation statements)

References 233 publications

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“…DUSPs possess a dual role in dephosphorylating phosphor-tyrosine and the phosphor-serine residues and belong to the classical cysteine-related protein phosphatases [ 31 ]. The implication of the DUSPs in neuronal differentiation and the neuronal diseases is shown in the previous reports [ 31 , 32 ].…”

Section: Resultsmentioning

confidence: 99%

Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells

Dayem

Lee

Choi

et al. 2018

IJMS

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We have previously demonstrated the potential of biologically synthesized silver nanoparticles (AgNP) in the induction of neuronal differentiation of human neuroblastoma, SH-SY5Y cells; we aimed herein to unveil its molecular mechanism in comparison to the well-known neuronal differentiation-inducing agent, all-trans-retinoic acid (RA). AgNP-treated SH-SY5Y cells showed significantly higher reactive oxygen species (ROS) generation, stronger mitochondrial membrane depolarization, lower dual-specificity phosphatase expression, higher extracellular-signal-regulated kinase (ERK) phosphorylation, lower AKT phosphorylation, and lower expression of the genes encoding the antioxidant enzymes than RA-treated cells. Notably, pretreatment with N-acetyl-l-cysteine significantly abolished AgNP-induced neuronal differentiation, but not in that induced by RA. ERK inhibition, but not AKT inhibition, suppresses neurite growth that is induced by AgNP. Taken together, our results uncover the pivotal contribution of ROS in the AgNP-induced neuronal differentiation mechanism, which is different from that of RA. However, the negative consequence of AgNP-induced neurite growth may be high ROS generation and the downregulation of the expression of the genes encoding the antioxidant enzymes, which prompts the future consideration and an in-depth study of the application of AgNP-differentiated cells in neurodegenerative disease therapy.

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Section: Resultsmentioning

confidence: 99%

Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells

Dayem

Lee

Choi

et al. 2018

IJMS

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“…Beyond the essential role in poxvirus infection, DUSPs are important regulators of many cellular signaling pathways. Many DUSP genes are implicated in human diseases affecting immunity and infection (37), cancer, muscle disorders, neurological (38), cardiovascular, and inflammatory diseases (39). The suit of methods described in our study may be useful for examining protein-protein interactions of these other enzyme-substrate combinations.…”

Section: Discussionmentioning

confidence: 98%

Peptide recognition and dephosphorylation by the vaccinia VH1 phosphatase

Zhao

Hogan

Lee

et al. 2020

Preprint

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The VH1 protein encoded by the highly conserved H1 locus of orthopoxviruses is a dualspecificity phosphatase (DUSPs) that hydrolyzes phosphate groups from phosphorylated tyrosine, serine, and threonine residues of viral and host cell proteins. Because the DUSP activities are required for virus replication, VH1 is a prime target for the development of therapeutic inhibitors. However, the presentation of a shallow catalytic site has thwarted all drug development efforts. As an alternative to direct targeting of catalytic pockets, we describe surface contacts between VH1 and substrates that are essential for full activity and provide a new pathway for developing inhibitors of proteinprotein interactions. Critical amino acid residues were manipulated by site-directed mutagenesis of VH1, and perturbation of peptide substrate interactions based on these mutations were assessed by high-throughput assays that employed surface plasmon resonance and phosphatase activities. Two positively-charged residues (Lys-20 and Lys-22) and the hydrophobic side chain of Met-60 appear to orient the polarity of the pTyr peptide on the VH1 surface, while additional amino acid residues that flank the catalytic site contribute to substrate recognition and productive dephosphorylation. We propose that the enzyme-substrate contact residues described here may serve as molecular targets for the development of inhibitors that specifically block VH1 catalytic activity and thus poxvirus replication. ____________________________________

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“…Dual-specificity phosphatases (DUSPs) are a family of phosphatases that can act on both serine/threonine and tyrosine residues of several protein substrates leading to wide-ranging effects on cellular signaling and biological processes. With the exact number of DUSP members still being controversial [7,58,59], we chose to consider the latest classification described by Chen et al [7], consisting of 40 DUSPs with 9 subfamilies containing more than one member. We validated the subfamily-based classification of DUSPs using two approaches namely-sequence alignment and SMART-based domain analysis.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Subbannayya

Pinto

Bösl

et al. 2019

Preprint

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Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focused on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSPmediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study has the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

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Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases

Cited by 25 publications

References 233 publications

Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells

Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells

Peptide recognition and dephosphorylation by the vaccinia VH1 phosphatase

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

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