<scp>VHR</scp>/<scp>DUSP</scp>3 phosphatase: structure, function and regulation

Pavic, Karolina; Duan, Guangyou; Köhn, Maja

doi:10.1111/febs.13263

Cited by 35 publications

(34 citation statements)

References 119 publications

(299 reference statements)

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“…196 The Vaccinia H1-related (VHR) phosphatase is a member of the DSP family shown to be important for the progression cell-cycle and tumorigenesis. 197 Functional analysis of the “variable insert” unique to VHR by incorporating para-benzoylphenylalanine, a photo-cross-linkable amino acid, led to the discovery that VHR can dimerize inside cells. 198 Further experiments indicate that VHR dimerization can lead to occlusion of its active site, blocking substrate accessibility.…”

Section: Ptp Regulatory Mechanismsmentioning

confidence: 99%

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Zhang

2017

Chem. Rev.

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Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic interventions. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination on a number of regulatory mechanisms including redox modulation, allosteric regulation, and protein oligomerization, in controlling PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.

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Section: Ptp Regulatory Mechanismsmentioning

confidence: 99%

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Zhang

2017

Chem. Rev.

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“…82, 90 Regardless, the actual biological functions of VHR are still poorly understood. (A more detailed survey of the literature can be found in a recent review by Pavic et al 91 )…”

Section: Vhr (Dusp3): Major Positive Regulator Of Platelet Signalimentioning

confidence: 99%

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy

Tautz

Senis

Oury

et al. 2015

Bioorganic & Medicinal Chemistry

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Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy.

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“…The functional connection between Dusp3 and Mapk pathways has remained controversial and it appears to be cell type and context specific . Therefore, in order to confirm that Dusp3 influences the Erk1/2 and Jnk pathways in our cell model, we transfected HeLa cells with siR‐control and siR‐Dusp3#2, and incubated the cells overnight with low 2% FBS containing growth medium.…”

Section: Resultsmentioning

confidence: 99%

“…There are 63 known Dusp proteins classified into seven subgroups namely mitogen‐activated protein kinase (Mapk) phosphatases (Mkps), atypical dual specificity phosphatases (A‐Dusps), phosphatases of regenerating liver, slingshots phosphatases, phosphatase and tensin homolog protein phosphatases, myotubularins, and Cell division cycle 14 homologues (Cdc14s). The Dusps regulate many cellular processes by targeting a variety of substrates such as mRNA, peptides, lipids and glycans .…”

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confidence: 99%

Reduced levels of Dusp3/Vhr phosphatase impair normal spindle bipolarity in an Erk1/2 activity‐dependent manner

2016

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Dual specificity phosphatase-3 (Dusp3/Vhr) regulates cell cycle progression by counteracting the effects of mitogen-activated protein kinases (Mapk) Erk1/2 and Jnk. Despite the known upregulation of Dusp3 at M phase in mammalian cells, its mitotic functions are poorly characterized. Here, we report that loss of Dusp3 by RNAi leads to the formation of multipolar spindles in human mitotic cancer cells in an Erk1/2-dependent manner. In the phosphatase-silenced cells, the normal bipolar spindle structure was restored by chemical inhibition of Erk1/2 and ectopic overexpression of Dusp3. We propose that at M phase Dusp3 keeps Erk1/2 activity in check to facilitate normal mitosis.

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VHR/DUSP3 phosphatase: structure, function and regulation

Cited by 35 publications

References 119 publications

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy

Reduced levels of Dusp3/Vhr phosphatase impair normal spindle bipolarity in an Erk1/2 activity‐dependent manner

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