A Functional Role for the B56 α-Subunit of Protein Phosphatase 2A in Ceramide-mediated Regulation of Bcl2 Phosphorylation Status and Function

Ruvolo, Peter P.; Clark, W. Lloyd; Mumby, Marc C.; Gao, Fengqin; May, W. Stratford

doi:10.1074/jbc.m201830200

Cited by 151 publications

(159 citation statements)

References 38 publications

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“…c-Myc interacts with the B56a subunit, and knock down of B56a can increase c-Myc protein expression levels. Dephosphorylation of Bcl-2 by PP2A through B56a appears to be required for ceramide-induced cell death (Ruvolo et al, 2002). Even in the presence of 2% NP-40, we find that the B56b subunit of PP2A interacts strongly with Pim-1.…”

Section: Regulation Ofmentioning

confidence: 59%

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

Arnold

Lilly

et al. 2007

Oncogene

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The Pim protein kinases are serine threonine protein kinases that regulate important cellular signaling pathway molecules, and enhance the ability of c-Myc to induce lymphomas. We demonstrate that a cascade of events controls the cellular levels of Pim. We find that overexpression of the protein phosphatase (PP) 2A catalytic subunit decreases the activity and protein levels of Pim-1. This effect is reversed by the application of okadaic acid, an inhibitor of PP2A, and is blocked by SV40 small T antigen that is known to disrupt B subunit binding to PP2A A and C subunits. Pim-1 can coimmunoprecipitate with the PP2A regulatory B subunit, B56b, but not B56a, c, d, e or B55a. Using short hairpin RNA targeted at B56b, we demonstrate that decreasing the level of B56b increases the half-life of Pim-1 from 0.7 to 2.8 h, and decreases the ubiquitinylation level of Pim-1. We also find that Pin1, a prolyl-isomerase, is capable of binding Pim-1 and leads to a decrease in the protein level of Pim-1. On the basis of these observations, we hypothesize that phosphorylated Pim-1 binds Pin1 allowing the interaction of PP2A through B56b. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.

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Section: Regulation Ofmentioning

confidence: 59%

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

Arnold

Lilly

et al. 2007

Oncogene

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show abstract

“…Protein phosphatase 2A not only preserves BCL-2 antiapoptotic activity, but also activates several proapoptotic BCL-2 family members (Chiang et al, 2001(Chiang et al, , 2003Puthalakath et al, 2007), and, in at least one system, has an inhibitory, as opposed to an activating, effect on BCL-2 (Ruvolo et al, 1999(Ruvolo et al, , 2002. These apparently contradictory results may be due to the involvement of substrate/organelle-specific PP2A regulatory subunits, stimulus-dependent phosphorylation site specificity or availability, or additional posttranslational modifications.…”

Section: Pathways Leading To Er Stress-induced Apoptosismentioning

confidence: 61%

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

2008

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“…11,12 PP2A is essential for apoptosis in cells with functional Bcl2. 13 PP2A also dephosphorylatively activates the pro-apoptotic factor, Bad, in a 14-3-3 protein-dissociation dependent manner in the context of cytokine-induced cell stress signaling. 14 On the other hand, PP2A confers resistance to apoptosis in highly metabolic cells through dephosphorylatively activating CaMKII, an inhibitory kinase of caspase-2, highlighting the dynamic processes in which PP2A activity promotes or inhibits apoptosis.…”

Section: Inhibition Of Wnt/beta-catenin Signalingmentioning

confidence: 99%

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Zhang

et al. 2015

Cancer Biology & Therapy

103

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A Functional Role for the B56 α-Subunit of Protein Phosphatase 2A in Ceramide-mediated Regulation of Bcl2 Phosphorylation Status and Function

Abstract: Recently it has been shown that the potent apoptotic agent ceramide activates a mitochondrial protein phosphatase 2A (PP2A) and promotes dephosphorylation of the anti-apoptotic molecule Bcl2 (Ruvolo, P. P., Deng, X., Ito, T., Carr, B. K., and May, W. S.

Cited by 151 publications

References 38 publications

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

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