Identification and H2O2 sensitivity of the major constitutive MAPK phosphatase from rat brain

Foley, Timothy D.; Armstrong, John J; Kupchak, Brian R.

doi:10.1016/j.bbrc.2004.01.096

Cited by 48 publications

(36 citation statements)

References 27 publications

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“…As such, in the clinical setting, it is possible that greater-than-normal ␤-adrenergic support of the acutely failing heart could occur if ␤-adrenergic activation of PP2a were inhibited. Some studies have demonstrated that H 2 O 2 treatment reduces PP2a activity through a glutathionylation of PP2a (11,31,35). However, other studies have shown that H 2 O 2 increases PP2a activity associated with specific PP2a substrates in cells (5,25).…”

Section: Discussionmentioning

confidence: 99%

Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor

Deshmukh

Blunt

Hofmann³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Deshmukh PA, Blunt BC, Hofmann PA. Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor. Am J Physiol Heart Circ Physiol 292: H792-H799, 2007. First published September 29, 2006; doi:10.1152/ajpheart.00225.2006.-The present study demonstrates that acute activation with either ␤-adrenergic receptor agonists or H2O2 treatment increases protein phosphatase 2a (PP2a) activity in ventricular myocytes. PP2a activation occurs concomitant with an increase in methylation of PP2a, changes in localization of a PP2a targeting subunit PP2aB56␣, and a decrease in phosphorylation of PP2a substrates, such as troponin I (TnI) and ERK in ventricular myocytes. Okadaic acid, a well-established pharmacological inhibitor of PP2a, and the peptide Thr-Pro-AspTyr-Phe-Leu (TPDYFL) were used to block PP2a methylation, localization, and phosphorylations. TPDYFL is a highly conserved sequence of the PP2a catalytic subunit COOH-terminus. Specifically, both okadaic acid and the peptide increased ␤-adrenergiccAMP-dependent phosphorylation of TnI and blocked the ␤-adrenergic-cAMP-dependent translocation of PP2aB56␣. TPDYFL, but not a scrambled version of this sequence, blocked H2O2-induced changes in PP2a methylation and TnI dephosphorylation. Okadaic acid produces similar inhibition of H2O2 effects. Thus we propose that the novel peptide TPDYFL acts as an inhibitor of PP2a activity and may be a useful tool to increase our understanding of how PP2a is regulated and the role of PP2a in a variety of physiological and pathological processes. In addition, the present study is consistent with acute ␤-adrenergic receptor activation and H2O2 exposure, simultaneously activating kinases and PP2a to work on common substrates, such as TnI. We hypothesize that dual activation of opposing enzymes provides for a tighter regulation of substrate phosphorylations in ventricular myocytes.␤-adrenergic receptor; hydrogen peroxide; peptide inhibition; protein phosphatase 2a

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Section: Discussionmentioning

confidence: 99%

Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor

Deshmukh

Blunt

Hofmann³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Although it is known that PP2A is regulated by phosphorylation and methylation of the catalytic subunit, some studies indicate that PP2A may be regulated by redox modification of cysteine residues in the same way that PTPs are inactivated by oxidant modification of a cysteine in the catalytic domain (29,30). Other studies, using brain, cultured T cells, and fibroblasts have shown that the oxidant stress hydrogen peroxide can increase ERK activity via a decrease in phosphatase activity, including PP2A and protein/tyrosine phosphatases (29,42,43). Inhibition of PP2A by okadaic acid, an inhibitor of protein serine/threonine phosphatase, can result in activation of ERK (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…Hyperoxia Decreases PP2A and MKP-3 Activity for ERK Dephosphorylation-It is known that oxidant stimuli, such as hydrogen peroxide, decrease activity of some phosphatases, resulting in ERK activation (29,42,43 2 ) for 24 h. Immunoprecipitation was performed by incubation of the whole cell lysates with antibodies for PP2A or MKP-3. Immunoprecipitated PP2A or MKP-3 was incubated with recombinant pERK in phosphatase buffer at 37°C for 20 min.…”

Section: Hyperoxia-induced Erk Activation Is Not Associated With Incrmentioning

confidence: 99%

Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation

Nyunoya

Monick

Powers

et al. 2005

Journal of Biological Chemistry

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Macrophages exposed to hyperoxia in the lung continue to survive for prolonged periods. We previously reported (Nyunoya, T., Powers, L. S., Yarovinsky, T. O., Butler, N. S., Monick, M. M., and Hunninghake, G. W. (2003) J. Biol. Chem. 278, 36099 -36106) that hyperoxia induces cell cycle arrest and sustained extracellular signal-related kinase (ERK) activity in macrophages. In this study, we determined the mechanisms of hyperoxiainduced ERK activation and how ERK activity plays a pro-survival role in hyperoxia-exposed cells. Inhibition of ERK activity decreased survival of hyperoxia-exposed macrophages. This was due, at least in part, to down-regulation of the pro-apoptotic Bcl-2 family member, BimEL. In determining the mechanism of ERK activation by hyperoxia, we found that ERK activation was not associated with hyperoxia-induced activation of the upstream ERK kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2. When we examined the ability of whole cell lysates from hyperoxia-exposed cells to dephosphorylate purified phosphorylated ERK, we found decreased ERK-directed phosphatase activity. Two particular ERK-directed phosphatases (protein phosphatase 2A and MAPK phosphatase-3) demonstrated decreased activity in hyperoxia-exposed cells. Moreover, whole cell lysates from normoxia-exposed cells depleted of PP2A or MAPK phosphatase-3 were also less able to dephosphorylate ERK. These data demonstrate that, in hyperoxia-exposed macrophages, sustained activation of ERK due to phosphatase down-regulation permits macrophage survival via effects on the balance between pro-and antiapoptotic Bcl-2 family proteins.

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“…Inhibition of MAP kinase phosphatase-3, a tyrosine phosphatase that is specific for p42/44 MAPK, has been shown to play a key role in mediating the activation and nuclear localization of p42/44 MAPK in states of oxidative stress (42). In addition, the inhibition of the protein tyrosine phosphatases SHP-1 and HePTP and the serine/threonine phosphatase PP2A have also been shown to mediate p42/44 MAPK activation by H 2 O 2 (43,44). As there is some evidence that PP2A is a substrate of mTOR and the state of phosphorylation of the S6Ks and S6 are exquisitely sensitive to rapamycin inhibition of mTOR activity (45), it is possible that phosphatase inhibition directly due to mTOR activation partially accounts for the MAPK activation that occurs in TSC2À/À cells in response to PDGF.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived Growth Factor–Induced p42/44 Mitogen-Activated Protein Kinase Activation and Cellular Growth Is Mediated by Reactive Oxygen Species in the Absence of TSC2/Tuberin

Finlay

Thannickal²,

Fanburg³

et al. 2005

Cancer Research

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Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively. TSC is characterized by multiple tumors of the brain, kidney, heart, and skin. Tuberin and hamartin inhibit signaling by the mammalian target of rapamycin (mTOR) but there are limited studies of their involvement in other pathways controlling cell growth. Using ELT-3 cells, which are Eker rat-derived smooth muscle cells, we show that ELT-3 cells expressing tuberin (TSC2+/+) respond to platelet-derived growth factor (PDGF) stimulation by activating the classic mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase (MEK)-1-dependent phosphorylation of p42/44 MAP kinase (MAPK) with nuclear translocation of phosphorylated p42/44 MAPK. In contrast, in tuberin-deficient ELT-3 cells (TSC2À/À), PDGF stimulation results in MEK-1-independent p42/44 MAPK phosphorylation with reduced nuclear localization of phosphorylated p42/44 MAPK. Moreover, in TSC2À/À cells but not in TSC2+/+ cells, cellular growth and activation of p42/44 MAPK by PDGF requires the reactive oxygen species intermediate, superoxide anion (O 2 Á À ). Both baseline and PDGF-induced O 2 Á À levels were significantly higher in TSC2À/À cells and were reduced by treatment with rapamycin and inhibitors of mitochondrial electron transport. Furthermore, the exogenous production of O 2 Á À by the redox cycling compound menadione induced MEK-1-independent cellular growth and p42/44 MAPK phosphorylation in TSC2À/À cells but not in TSC2+/+ cells. Together, our data suggest that loss of tuberin, which causes mTOR activation, leads to a novel cellular growth-promoting pathway involving mitochondrial oxidant-dependent p42/44 MAPK activation and mitogenic growth responses to PDGF. (Cancer Res 2005; 65(23): 10881-90)

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Identification and H2O2 sensitivity of the major constitutive MAPK phosphatase from rat brain

Cited by 48 publications

References 27 publications

Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor

Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor

Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation

Platelet-Derived Growth Factor–Induced p42/44 Mitogen-Activated Protein Kinase Activation and Cellular Growth Is Mediated by Reactive Oxygen Species in the Absence of TSC2/Tuberin

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