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PMID:16717086
| Citation |
Lin, SS, Bassik, MC, Suh, H, Nishino, M, Arroyo, JD, Hahn, WC, Korsmeyer, SJ and Roberts, TM (2006) PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum. J. Biol. Chem. 281:23003-12 |
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| Abstract |
Anti-apoptotic activity of BCL-2 is mediated by phosphorylation at the endoplasmic reticulum (ER), but how this phosphorylation is regulated and the mechanism(s) by which it regulates apoptosis are unknown. We purified macromolecular complexes containing BCL-2 from ER membranes and found that BCL-2 co-purified with the main two subunits of the serine/threonine phosphatase, PP2A. The association of endogenous PP2A and BCL-2 at the ER was verified by co-immunoprecipitation and microcystin affinity purification. Knock down or pharmacological inhibition of PP2A caused degradation of phosphorylated BCL-2 and led to an overall reduction in BCL-2 levels. We found that this degradation was due to the action of the proteasome acting selectively at the ER. Conversely, overexpression of PP2A caused elevation in endogenous BCL-2. Most importantly, we found that PP2A knock down sensitized cells to several classes of death stimuli (including ER stress), but this effect was abolished in a genetic background featuring knock in of a non-phosphorylatable BCL-2 allele. These studies support the hypothesis that PP2A-mediated dephosphorylation of BCL-2 is required to protect BCL-2 from proteasome-dependent degradation, affecting resistance to ER stress. |
| Links |
PubMed Online version:10.1074/jbc.M602648200 |
| Keywords |
Amino Acid Sequence; Animals; Apoptosis; Endoplasmic Reticulum/metabolism; Gene Expression Regulation; Humans; Jurkat Cells; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Phosphoprotein Phosphatases/metabolism; Phosphoprotein Phosphatases/physiology; Phosphorylation; Proteasome Endopeptidase Complex/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; Sequence Homology, Amino Acid |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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