Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress

Morita, Keiichi; Saitoh, Masao; Tobiume, Kei; Matsuura, Hiroshi; Enomoto, Shoji; Nishitoh, Hideki; Ichijo, Hidenori

doi:10.1093/emboj/20.21.6028

Cited by 282 publications

(279 citation statements)

References 57 publications

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“…Limited phosphorylation was seen on Thr, and none was detected on Tyr. Our results are consistent with earlier findings (Ichijo et al, 1997;Morita et al, 2001) and demonstrate that ASK1 is phosphorylated in COS7 and HeLa cells when grown in the presence of serum.…”

supporting

confidence: 94%

“…The apoptotic cells were scored based on the phenomenon that cells undergoing apoptosis shrink and show round-up shape before detaching from culture dishes (Chen et al, 2001). Consistent with previous reports (Ichijo et al, 1997;Morita et al, 2001), overexpression of ASK1 WT was able to induce apoptosis in COS7 cells and the mutant ASK1/S967A, which is defective in 14-3-3 binding, showed increased apoptotic activity (Figure 1a). Interestingly, the ASK1/S1034A mutant, which abolishes the Ser-1034 phosphorylation site, exhibited enhanced proapoptotic activity, similar to that induced by ASK1/S967A.…”

Section: Mutating Ser-1034 To Ala Is Associated With An Enhanced Deatsupporting

confidence: 72%

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Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034

et al. 2004

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supporting

confidence: 94%

Section: Mutating Ser-1034 To Ala Is Associated With An Enhanced Deatsupporting

confidence: 72%

Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034

et al. 2004

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“…Phosphorylation at Thr-838 leads to activation of ASK1, whereas phosphorylation at Ser-83, Ser-967, or Ser-1034 inactivates ASK1. 24,[26][27][28] ASK1 is basally phosphorylated at Ser-967 by an unidentified kinase, and 14-3-3 binds to this site to inhibit ASK1. 24 Phosphorylation at Ser-83 is known to be catalyzed by Akt or PIM1.…”

mentioning

confidence: 99%

“…31 Several phosphatases that dephosphorylate some of these sites have been identified. Serine/threonine protein phosphatase type 5 (PP5) and PP2C dephosphorylate phosphorylated (p)-Thr-838, 28,32 whereas PP2A and SHP2 dephosphorylate p-Ser-967 and p-Tyr-718, respectively. 31,33 Little is known about the kinase or phosphatase that regulates phosphorylation at Ser-1034.…”

mentioning

confidence: 99%

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

Cho

Park

et al. 2015

Cell Death Differ

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Cdc25C (cell division cycle 25C) phosphatase triggers entry into mitosis in the cell cycle by dephosphorylating cyclin B-Cdk1. Cdc25C exhibits basal phosphatase activity during interphase and then becomes activated at the G 2 /M transition after hyperphosphorylation on multiple sites and dissociation from 14-3-3. Although the role of Cdc25C in mitosis has been extensively studied, its function in interphase remains elusive. Here, we show that during interphase Cdc25C suppresses apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein (MAP) kinase kinase kinase family that mediates apoptosis. Cdc25C phosphatase dephosphorylates phospho-Thr-838 in the activation loop of ASK1 in vitro and in interphase cells. In addition, knockdown of Cdc25C increases the activity of ASK1 and ASK1 downstream targets in interphase cells, and overexpression of Cdc25C inhibits ASK1-mediated apoptosis, suggesting that Cdc25C binds to and negatively regulates ASK1. Furthermore, we showed that ASK1 kinase activity correlated with Cdc25C activation during mitotic arrest and enhanced ASK1 activity in the presence of activated Cdc25C resulted from the weak association between ASK1 and Cdc25C. In cells synchronized in mitosis following nocodazole treatment, phosphorylation of Thr-838 in the activation loop of ASK1 increased. Compared with hypophosphorylated Cdc25C, which exhibited basal phosphatase activity in interphase, hyperphosphorylated Cdc25C exhibited enhanced phosphatase activity during mitotic arrest, but had significantly reduced affinity to ASK1, suggesting that enhanced ASK1 activity in mitosis was due to reduced binding of hyperphosphorylated Cdc25C to ASK1. These findings suggest that Cdc25C negatively regulates proapoptotic ASK1 in a cell cycle-dependent manner and may play a role in G 2 /M checkpointmediated apoptosis.

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“…Notably, PP5 has been shown to associate with several proteins that affect signal transduction networks [1][2][3][4][5][6][14][15][16][17][18]. When PP5 is displaced from these biological partners, phosphatase activity is greatly decreased.…”

Section: Expression and Purification Of Pp5cmentioning

confidence: 99%

High Yield Expression of Serine/Threonine Protein Phosphatase Type 5, and a Fluorescent Assay Suitable for Use in the Detection of Catalytic Inhibitors

Swingle

Bourgeois

et al. 2007

ASSAY and Drug Development Technologies

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Protein phosphatase type 5 (PP5) belongs to the PPP-family of serine/threonine protein phosphatases and is expressed in most, if not all, human tissues. Although the physiological roles played by PP5are not yet clear, PP5 is found in association with several proteins that influence intracellular signaling networks initiated by hormones (i.e. glucocorticoids) or cellular stress (i.e. hypoxia, oxidative stress). Recently, studies conducted with siRNA and antisense oligonucleotides indicate that PP5 plays an important role in the regulation of stress-induced signaling cascades that influence both cell growth and the onset of apoptosis. Therefore, the identification of small molecule inhibitors of PP5 is desired for use in studies to further define the biological/pathological roles of PP5. Such inhibitors may also prove useful for development into novel antitumor agents. Here we describe methods to express and purify large amounts of biologically active PP5c, an inhibitor-titration based assay to determine the amount of PP5 in solution, and a fluorescent phosphatase assay that can be used to screen chemical libraries and natural extracts for the presence of catalytic inhibitors.

show abstract

Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress

Cited by 282 publications

References 57 publications

Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034

Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

High Yield Expression of Serine/Threonine Protein Phosphatase Type 5, and a Fluorescent Assay Suitable for Use in the Detection of Catalytic Inhibitors

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