PP1/PP2A phosphatases inhibitors okadaic acid and calyculin A block ERK5 activation by growth factors and oxidative stress

Garcia, Lourdes; García, Fernández; Llorens, Franc; Unzeta, Mercedes; Itarte, Emilio; Gómez, Néstor

doi:10.1016/s0014-5793(02)02950-2

Cited by 46 publications

(39 citation statements)

References 16 publications

(20 reference statements)

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“…Okadaic acid, a specific inhibitor of the PP1 and PP2A Ser/Thr phosphatases, has been demonstrated to block the activation of ERK5 that occurs in HeLa cells exposed to EGF or H 2 O 2 as well as in PC12 cells stimulated by nerve growth factor or H 2 O 2 (25). As shown in Fig.…”

Section: Tyrosine Phosphatases the Ser/thr Phosphatases Pp1 And Pp2amentioning

confidence: 88%

“…3A, the treatment of BAC1.2F5 cells with orthovanadate, a PTP inhibitor, or okadaic acid did not affect CSF-1-induced ERK5 phosphorylation or modify its kinetics (data not shown), suggesting that okadaic acid-sensitive phosphatases or PTP are not involved in ERK5 dephosphorylation. PKC has been demonstrated to act as a negative regulator of the ERK5 activation pathway (25). CSF-1 has been reported to activate PKC, or at least PKC-␣ and -␦ (26,27), although PKC is not involved in CSF-1-induced ERK1/2 activation (28).…”

Section: Tyrosine Phosphatases the Ser/thr Phosphatases Pp1 And Pp2amentioning

confidence: 99%

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ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion

Rovida

Spinelli

Sdelci

et al. 2008

The Journal of Immunology

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CSF-1, by binding to its high-affinity receptor CSF-1R, sustains the survival and proliferation of monocyte/macrophages, which are central cells of innate immunity and inflammation. The MAPK ERK5 (also known as big MAPK-1, BMK1, or MAPK7) is a 98-kDa molecule sharing high homology with ERK1/2. ERK5 is activated by oxidative stress or growth factor stimulation. This study was undertaken to characterize ERK5 involvement in macrophage signaling that is elicited by CSF-1. Exposure to the CSF-1 of primary human macrophages or murine macrophage cell lines, as well as murine fibroblasts expressing ectopic CSF-1R, resulted in a rapid and sustained increase of ERK5 phosphorylation on activation-specific residues. In the BAC1.2F5 macrophage cell line, ERK5 was also activated by another mitogen, GM-CSF, while macrophage activators such as LPS or IFN-γ and a number of nonproliferative cytokines failed. Src family kinases were found to link the activation of CSF-1R to that of ERK5, whereas protein kinase C or the serine phosphatases PP1 and PP2A seem not to be involved in the process. Treatment of macrophages with ERK5-specific small interfering RNA markedly reduced CSF-1-induced DNA synthesis and total c-Jun phosphorylation and expression, while increasing the expression of the cyclin-dependent kinase inhibitor p27. Following CSF-1 treatment, the active form of ERK5 rapidly translocated from cytosol to nucleus. Taken together, the results reported in this study show that ERK5 is indispensable for optimal CSF-1-induced proliferation and indicate a novel target for its control.

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Section: Tyrosine Phosphatases the Ser/thr Phosphatases Pp1 And Pp2amentioning

confidence: 88%

Section: Tyrosine Phosphatases the Ser/thr Phosphatases Pp1 And Pp2amentioning

confidence: 99%

ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion

Rovida

Spinelli

Sdelci

et al. 2008

The Journal of Immunology

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“…ERKs are activated by phosphorylation of both conserved threonine and tyrosine residues and inactivated on dephosphorylation by specific phosphatases (15)(16)(17)(18)(19)(20). Serine-threonine PP2A can dephosphorylate MEKand ERK-family kinases in vitro (21,22).…”

Section: Discussionmentioning

confidence: 99%

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

Yoon

Kim

Park

et al. 2009

Molecular Cancer Research

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Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor -independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein kinase (MAPK) activation and that suppression of the MAPK/extracellular signal -regulated kinase (ERK) kinase/ERK pathway by protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor -independent caspase-8 activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation. PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor -independent activation of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid metabolites.

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“…Although okadaic acid at high concentrations can inhibit PP1 as well as PP2A, it is well documented that dephosphorylation of TH Ser40 occurs almost exclusively by PP2A, not by PP1 activity (Berresheim and Kuhn, 1994;Dunkley et al, 2004;Haavik et al, 1989;Leal et al, 2002). Furthermore, we treated cells with low to high dose okadaic acid (5 nM-1 μM) dissolved in DMSO (0.13 μM) (Garcia et al, 2002;Haavik et al, 1989) for 1 hour to assess the impact on PP2A inhibition in the presence of α-Syn overexpression and saw a similar effect. For baseline TH Ser40 phosphorylation, cells were treated with 0.13 μM DMSO for 1 hour without okadaic acid.…”

Section: Okadaic Acid Treatmentmentioning

confidence: 99%

α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells

Peng

Tehranian

Dietrich

et al. 2005

Journal of Cell Science

232

211

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α-Synuclein is an abundant presynaptic protein implicated in neuronal plasticity and neurodegenerative diseases. Although the function of α-synuclein is not thoroughly elucidated, we found that α-synuclein regulates dopamine synthesis by binding to and inhibiting tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. Understanding α-synuclein function in dopaminergic cells should add to our knowledge of this key protein, which is implicated in Parkinson's disease and other disorders. Herein, we report a mechanism by which α-synuclein diminishes tyrosine hydroxylase phosphorylation and activity in stably transfected dopaminergic cells. Short-term regulation of tyrosine hydroxylase depends on the phosphorylation of key seryl residues in the amino-terminal regulatory domain of the protein. Of these, Ser40 contributes significantly to tyrosine hydroxylase activation and dopamine synthesis. We observed that α-synuclein overexpression caused reduced Ser40 phosphorylation in MN9D cells and inducible PC12 cells. Ser40 is phosphorylated chiefly by the cyclic AMP-dependent protein kinase PKA and dephosphorylated almost exclusively by the protein phosphatase, PP2A. Therefore, we measured the impact of α-synuclein overexpression on levels and activity of PKA and PP2A in our cells. PKA was unaffected by α-synuclein. PP2A protein levels also were unchanged, however, the activity of PP2A increased in parallel with α-synuclein expression. Inhibition of PP2A dramatically increased Ser40 phosphorylation only in α-synuclein overexpressors in which α-synuclein was also found to co-immunoprecipitate with PP2A. Together the data reveal a functional interaction between α-synuclein and PP2A that leads to PP2A activation and underscores a key role for α-synuclein in protein phosphorylation.

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PP1/PP2A phosphatases inhibitors okadaic acid and calyculin A block ERK5 activation by growth factors and oxidative stress

Cited by 46 publications

References 16 publications

ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion

ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells

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