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Theodosiou, Aspasia; Ashworth, Alan

doi:10.1186/gb-2002-3-7-reviews3009

Cited by 278 publications

(109 citation statements)

References 69 publications

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“…2,3 Also known as mitogenactivated protein kinase phosphatase 3 (MKP3), DUSP6 additionally plays a key role in regulating extracellular signal-regulated kinase (ERK) 1/2 pathway which is implicated in pathophysiology of major psychiatric disorders. 4,5 Although Toyota et al (2000) reported a lack of association between Japanese bipolar patients and T/G polymorphism (rs2279574, Leu114Val) in DUSP6 gene, 6 a number of recent findings strongly suggests the involvement of DUSP6 in mediating psychiatric manifestations. For example, DUSP6 mRNA increases after electroconvulsive seizure in rat brain.…”

mentioning

confidence: 99%

The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

Joo

et al. 2006

Mol Psychiatry

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confidence: 99%

The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

Joo

et al. 2006

Mol Psychiatry

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“…Dual specificity (Thr/Tyr) protein phosphatases play an important role in the regulation of signaling by mitogen-activated protein (MAP) 1 kinases in eukaryotic cells (1)(2)(3). These MAP kinase phosphatases (MKPs) act in direct opposition to the MAP kinase kinases (MKKs or MEKs) to dephosphorylate and inactivate the MAP kinase, thus regulating the duration and magnitude of activation and hence the biological outcome of signaling.…”

mentioning

confidence: 99%

“…There are 10 distinct MKPs in mammalian cells (3), and these enzymes feature a common structure comprising a carboxyl-terminal catalytic domain with sequence similarity to the prototypic VH1 dual specificity phosphatase of vaccinia virus (8) and an amino-terminal noncatalytic domain containing two short regions of homology with the cell cycle regulatory phosphatase cdc25 (9). MKPs can be subdivided into three main groups based on sequence similarity, gene regulation, and subcellular localization (1)(2)(3).…”

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confidence: 99%

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Both Nuclear-Cytoplasmic Shuttling of the Dual Specificity Phosphatase MKP-3 and Its Ability to Anchor MAP Kinase in the Cytoplasm Are Mediated by a Conserved Nuclear Export Signal

Karlsson

Mathers

Dickinson

et al. 2004

Journal of Biological Chemistry

119

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MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. However, the molecular basis of the cytoplasmic localization of MKP-3 or its physiological significance is unknown. We have used MKP-3-green fluorescent protein fusions in conjunction with leptomycin B to show that the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway. Furthermore, the nuclear translocation of MKP-3 seen in the presence of leptomycin B is mediated by an active process, indicating that MKP-3 shuttles between the nucleus and cytoplasm. The aminoterminal noncatalytic domain of MKP-3 is both necessary and sufficient for nuclear export of the phosphatase and contains a single functional leucine-rich nuclear export signal (NES). Even though this domain of the protein also mediates the binding of MKP-3 to MAP kinase, we show that mutations of the kinase interaction motif which abrogate ERK2 binding do not affect MKP-3 localization. Conversely, mutation of the NES does not affect either the binding or phosphatase activity of MKP-3 toward ERK2, indicating that the kinase interaction motif and NES function independently. Finally, we demonstrate that the ability of MKP-3 to cause the cytoplasmic retention of ERK2 requires both a functional kinase interaction motif and NES. We conclude that in addition to its established function in the regulated dephosphorylation and inactivation of MAP kinase, MKP-3 may also play a role in determining the subcellular localization of its substrate. Our results reinforce the idea that regulatory proteins such as MKP-3 may play a key role in the spatio-temporal regulation of MAP kinase activity.Dual specificity (Thr/Tyr) protein phosphatases play an important role in the regulation of signaling by mitogen-activated protein (MAP) 1 kinases in eukaryotic cells (1-3). These MAP kinase phosphatases (MKPs) act in direct opposition to the MAP kinase kinases (MKKs or MEKs) to dephosphorylate and inactivate the MAP kinase, thus regulating the duration and magnitude of activation and hence the biological outcome of signaling. Studies in Saccharomyces cerevisiae, Drosophila, and chicken embryos have also demonstrated that the expression of certain MKPs is induced in response to MAP kinase activation, indicating that they are components of negative feedback loops (4 -6). Furthermore, mathematical modeling of MAP kinase pathway dynamics emphasizes the role of MKPs in determining the timing and duration of MAP kinase activation in terms of bistable (switch-like) or monostable (proportional) response to agonists (7).There are 10 distinct MKPs in mammalian cells (3), and these enzymes feature a common structure comprising a carboxyl-terminal catalytic domain with sequence similarity to the prototypic VH1 dual specificity phosphatase of vaccinia virus (8) and an amino-terminal noncatalytic domain containing two short regions of homology with the cell ...

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“…The classic MKPs are a family of ten dual specificity threonine/tyrosine phosphatases that differ in tissue distribution, MAP kinase specificity, and subcellular distribution (41). Some MKPs are exclusively nuclear, others localize to the cytosol or shuttle between nucleus and cytosol.…”

Section: Erk1/2 Activated By Nk1-␤-arrestin1 Is Less Susceptible To Dmentioning

confidence: 99%

Constitutive ERK1/2 Activation by a Chimeric Neurokinin 1 Receptor-β-Arrestin1 Fusion Protein

Jafri

El‐Shewy

Lee

et al. 2006

Journal of Biological Chemistry

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The ␤-arrestins, a small family of G protein-coupled receptor (GPCR)-binding proteins involved in receptor desensitization, have been shown to bind extracellular signal-regulated kinases 1 and 2 (ERK1/2) and function as scaffolds for GPCR-stimulated ERK1/2 activation. To better understand the mechanism of ␤-arrestin-mediated ERK1/2 activation, we compared ERK1/2 activation by the wild-type neurokinin 1 (NK1) receptor with a chimeric NK1 receptor having ␤-arrestin1 fused to the receptor C terminus (NK1-␤Arr1). The NK1 receptor couples to both G s and G q/11 , resides on the plasma membrane, and mediates rapid ERK1/2 activation and nuclear translocation in response to neurokinin A. In contrast, NK1-␤Arr1 is a G protein-uncoupled "constitutively desensitized" receptor that resides almost entirely in an intracellular endosomal compartment. Despite its inability to respond to neurokinin A, we found that NK1-␤Arr1 expression caused robust constitutive activation of cytosolic ERK1/2 and that endogenous Raf, MEK1/2, and ERK1/2 coprecipitated in a complex with NK1-␤Arr1. While agonist-dependent ERK1/2 activation by the NK1 receptor was independent of protein kinase A (PKA) or PKC activity, NK1-␤Arr1-mediated ERK1/2 activation was completely inhibited when basal PKA and PKC activity were blocked. In addition, the rate of ERK1/2 dephosphorylation was slowed in NK1-␤Arr1-expressing cells, suggesting that ␤-arrestinbound ERK1/2 is protected from mitogen-activated protein kinase phosphatase activity. These data suggest that ␤-arrestin binding to GPCRs nucleates the formation of a stable "signalsome" that functions as a passive scaffold for the ERK1/2 cascade while confining ERK1/2 activity to an extranuclear compartment.

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Cited by 278 publications

References 69 publications

The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

Both Nuclear-Cytoplasmic Shuttling of the Dual Specificity Phosphatase MKP-3 and Its Ability to Anchor MAP Kinase in the Cytoplasm Are Mediated by a Conserved Nuclear Export Signal

Constitutive ERK1/2 Activation by a Chimeric Neurokinin 1 Receptor-β-Arrestin1 Fusion Protein

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