Protein phosphatase 1α is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis

Ayllón, Verónica; Martı́nez-A, Carlos; García, Alphonse; Cayla, Xavier; Rebollo, Angelita

doi:10.1093/emboj/19.10.2237

Cited by 143 publications

(116 citation statements)

References 56 publications

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“…Combined depletion of ASAH1 and Akt2 resulted in 73% inhibition of invasion. Similar results were obtained with PC3 cells where the inhibition of invasion was 44, 64 and 87% for ASAH1, Akt2 and ASAH1 + Akt2, pro-apoptotic roles via dephosphorylating RB, [53][54][55] Bad, 56 Bax, 57 caspase-9 58 and T450 in Akt. 59 Therefore, inhibition of both Akt and ASAH1 would be predicted to result in maximal dephosphorylation of key regulators of the malignant phenotype.…”

Section: Resultssupporting

confidence: 85%

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Berndt¹,

Patel²,

Yang³

et al. 2013

Cell Cycle

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Section: Resultssupporting

confidence: 85%

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Berndt¹,

Patel²,

Yang³

et al. 2013

Cell Cycle

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“…We have also shown that IL-2 deprivation-induced apoptosis operates by regulating Bad dephosphorylation through the PP1␣ phosphatase (37). In this article, we demonstrate that PP1␣ is associates with caspase-9 to induce its dephosphorylation and, as a consequence, its protease activity.…”

Section: Identification Of Pp1␣ As a Caspase-9 Regulator In Il-2 Deprmentioning

confidence: 62%

Identification of PP1α as a Caspase-9 Regulator in IL-2 Deprivation-Induced Apoptosis

Dessauge

Cayla

Albar

et al. 2006

The Journal of Immunology

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One of the mechanisms that regulate cell death is the reversible phosphorylation of proteins. ERK/MAPK phosphorylates caspase-9 at Thr125, and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr125 dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1α (PP1α) associates with phosphorylated caspase-9. IL-2 deprivation induces PP1α dephosphorylation, which leads to its activation and, as a consequence, dephosphorylation and activation of caspase-9 and subsequent dissociation of both molecules. In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1α is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation. Moreover, PP1α associates with caspase-9 in vitro and in vivo, suggesting that it is the phosphatase responsible for caspase-9 dephosphorylation and activation. Finally, we describe two novel phosphatase-binding sites different from the previously described PP1α consensus motifs, and we demonstrate that these novel sites mediate the interaction of PP1α with caspase-9.

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“…PP-1 dephosphorylates p53 in vivo As PP-1cas and p53 form complex in vivo and PP-1cas can directly dephosphorylate p53 in vitro, we next conducted an in vivo dephosphorylation assay, a procedure developed by Ayllon et al (2000). HLECs were labeled with [ 32 P]orthophosphate (200 mCi/ml) in phosphatase-free MEM and also subjected to UVA irradiation for 2 h. Under UVA irradiation, both Ser-15…”

Section: Pp-1cas Indirectly Interacts With P53 In Hlecsmentioning

confidence: 99%

“…In vivo dephosphorylation assays The in vivo dephosphorylation assays were conducted as described before (Ayllon et al, 2000). Briefly, HLECs were labeled with [ 32 P]orthophosphate (200 mCi/ml) in phosphatasefree DMEM and subjected to UVA irradiation for 2 h (UVA irradiation induces p53 phosphorylation at both Ser-15 and Ser-37 residues).…”

Section: In Vitro Binding Assay Of Pp-1cas and P53mentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

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We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

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Protein phosphatase 1α is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis

Cited by 143 publications

References 56 publications

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Identification of PP1α as a Caspase-9 Regulator in IL-2 Deprivation-Induced Apoptosis

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

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