Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits
- 19 March 2002
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 99 (7) , 4221-4226
- https://doi.org/10.1073/pnas.072071699
Abstract
Individual subunits of protein phosphatase 2A (PP2A), protein phosphatase 4, and protein phosphatase 5 were knocked out in Drosophila Schneider 2 cells by using RNA interference. Ablation of either the scaffold (A) or catalytic (C) subunits of PP2A caused the disappearance of all PP2A subunits. Treating cells with double-stranded RNA targeting all four of the Drosophila PP2A regulatory subunits caused the disappearance of both the A and C subunits. The loss of PP2A subunits was associated with decreased protein stability indicating that only the heterotrimeric forms of PP2A are stable in intact cells. Ablation of total PP2A by using double-stranded RNA against either the A or C subunit, or specific ablation of the R2/B regulatory subunit, enhanced insulin-induced ERK activation. These results indicated that the R2/B subunit targets PP2A to the mitogen-activated protein (MAP) kinase cascade in Schneider 2 cells, where it acts as a negative regulator. A severe loss of viability occurred in cells in which total PP2A or both isoforms of the Drosophila R5/B56 subunit had been ablated. The reduced viability of these cells correlated with the induction of markers of apoptosis including membrane blebbing and stimulation of caspase-3-like activity. These observations indicated that PP2A has a powerful antiapoptotic activity that is specifically mediated by the R5/B56 regulatory subunits. In contrast to PP2A, ablation of protein phosphatase 4 caused only a slight reduction in cell growth but had no effect on MAP kinase signaling or apoptosis. Depletion of protein phosphatase 5 had no effects on MAP kinase, cell growth, or apoptosis.Keywords
This publication has 66 references indexed in Scilit:
- Selective left-lobe atrophy by nodularin treatment accompanied by reduced protein phosphatase 1/2a and increased peroxisome proliferation in rat liverInternational Journal of Cancer, 2000
- Adenovirus E4orf4 protein interacts with both Bα and B′ subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with BαOncogene, 2000
- Raf-1-associated Protein Phosphatase 2A as a Positive Regulator of Kinase ActivationJournal of Biological Chemistry, 2000
- The Tetratricopeptide Repeat Domain of Protein Phosphatase 5 Mediates Binding to Glucocorticoid Receptor Heterocomplexes and Acts as a Dominant Negative MutantJournal of Biological Chemistry, 1996
- Apoptotic Activity of REAPER Is Distinct from Signaling by the Tumor Necrosis Factor Receptor 1 Death DomainPublished by Elsevier ,1996
- Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell linesCurrent Biology, 1995
- The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferationCell, 1993
- Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinasesNature, 1991
- The structure of protein phosphatase 2A is as highly conserved as that of protein phosphatase IFEBS Letters, 1990
- In vivo activation of a microtubule‐associated protein kinase during meiotic maturation of the Xenopus oocyteEuropean Journal of Biochemistry, 1990