Dual specificity phosphatases: a gene family for control of MAP kinase function

Camps, Montserrat; Nichols, Anton; Arkinstall, Steve

doi:10.1096/fasebj.14.1.6

Cited by 740 publications

(715 citation statements)

References 87 publications

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“…In addition, we found that Cdc25A was a phosphatase both for phospho-ERK-2 and for phospho-EGFR (Vogt et al, 2001;. Several other p-ERK phosphatases have more recently been described and reviewed (Camps et al, 2000).…”

Section: Cellular Consequences Of K Vitamin Interaction With Ptpsmentioning

confidence: 65%

“…This class of PTP is important, as its members are overexpressed in tumors (Galaktionov et al, 1995b;Cangi et al, 2000;Hernandez et al, 2001), are involved in cell cycle control of Cdks (Camps et al, 2000), and are transcriptional targets of c-myc (Galaktionov et al, 1996). Inhibitors of PTPases represent a new approach to interference with the cell cycle and also a novel set of tools for dissecting the role of phosphatases in specific cellular signaling pathways.…”

Section: Future Directionsmentioning

confidence: 99%

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K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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Section: Cellular Consequences Of K Vitamin Interaction With Ptpsmentioning

confidence: 65%

Section: Future Directionsmentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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“…It has been shown that reactive oxygen species promotes the activation of MAPK proteins by inhibiting MAP kinase phosphatases [55]. These phosphatases can dephosphorylate both phosphorylated threonine and phosphorylated tyrosine (dual specificity) residues and inactivate MAPK signaling [56]. It has been shown that MKP-1 (a family of dual-specificity protein phosphatases) can inactivate all three major MAPKs, including ERK, JNK and p38 [57].…”

Section: Discussionmentioning

confidence: 99%

Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-κB signaling

Katiyar

Meeran

2007

Free Radical Biology and Medicine

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Obesity has been implicated in several diseases including cancer, however, the relationship of obesity and susceptibility to ultraviolet (UV) radiation-caused skin diseases has not been investigated. As UV-induced oxidative stress has been implicated in several skin diseases, we assessed the role of obesity on UVB-induced oxidative stress in genetically obese Lep ob /Lep ob (leptin-deficient) mice. Here, we report that chronic exposure to UVB (120 mJ/cm 2 ) resulted in greater oxidative stress in the skin of obese mice in terms of higher levels of H 2 O 2 and NO production, photo-oxidative damage of lipids and proteins, and greater depletion of antioxidant defense enzymes, like, glutathione, glutathione peroxidase and catalase. As UV-induced oxidative stress mediates activation of MAPK and NF-κB signaling pathways, we determined the effect of UVB on these pathways in obese mice. Exposure of obese mice to UVB resulted in phosphorylation of ERK1/2, JNK and p38 proteins of the MAPK family. Compared to wild-type mice, the obese mice exhibited higher levels of phosphorylation of these proteins, greater activation of NF-κB/p65, and higher levels of circulating proinflammatory cytokines, including TNF-α, IL-1-β and IL-6, on UVB irradiation. Together, our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVBinduced oxidative stress, and therefore may be a risk factor for skin diseases associated with UVBinduced oxidative stress.

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“…This rapid phosphorylation and dephosphorylation of ERK occurs prior to the induction of MKP expression and may thereby also involve other classes of protein phosphatases that can influence the ERK cascade (Camps et al, 2000). First, the protein serine/ threonine phosphatase, PP2A can dephosphorylate the phosphothreonine residue of MAP kinase.…”

Section: Discussionmentioning

confidence: 99%

Electroconvulsive Seizures Increase the Expression of MAP Kinase Phosphatases in Limbic Regions of Rat Brain

Kodama

Russell

Duman

2004

Neuropsychopharmacol

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The mitogen-activated protein (MAP) kinase cascades regulate a variety of cellular activities, including cell growth, proliferation, and apoptosis, and are reported to play a role in the actions of antidepressant treatment. There are a number of different classes of protein phosphatases that could influence the MAP kinase cascade. One of these, the MAP kinase phosphatase (MKP) family, is known to play a key role in dephosphorylation of activated MAP kinase. In the present study, we analyzed the expression of the MKP1, MKP2, and MKP3 isoforms in rat brain after electroconvulsive seizure (ECS), considered the most effective treatment for depression. In situ hybridization analysis demonstrates that ECS differentially regulates the expression of the MKP isoforms. Expression of MKP1 mRNA is robustly increased by acute ECS in the major cell layers of the hippocampus, including the dentate gyrus granule cell layer and the CA1 and CA3 pyramidal cell layers. In contrast, MKP2 is induced mainly in the dentate gyrus and MKP3 is preferentially increased in the CA1 and CA3 cell layers. In the prefrontal cortex, all three MKP isoforms are upregulated by acute ECS administration. Chronic ECS resulted in a similar pattern of induction for each of the MKP subtypes, demonstrating that there is little or no desensitization of the response to repeated ECS. The induction of MKP expression serves as negative feedback control for the MAP kinase cascades. Upregulation of MKP expression could dampen the actions of ECS, indicating that blockade of the MKPs could enhance the actions of antidepressant treatment.

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Dual specificity phosphatases: a gene family for control of MAP kinase function

Cited by 740 publications

References 87 publications

K vitamins, PTP antagonism, and cell growth arrest

K vitamins, PTP antagonism, and cell growth arrest

Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-κB signaling

Electroconvulsive Seizures Increase the Expression of MAP Kinase Phosphatases in Limbic Regions of Rat Brain

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