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Papers In Press, published online ahead of print May 22, 2006
Dept. of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115
Corresponding Author: thomas_roberts{at}dfci.harvard.edu
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/theronine phosphatase, PP2A. The association of endogenous PP2A and BCL-2 at the ER was verified by co-immunoprecipitation and microcystin affinity purification. Knockdown 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 knockdown sensitized cells to several classes of death stimuli (including ER stress), but this effect was abolished in a genetic background featuring knockin 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.
J. Biol. Chem, 10.1074/jbc.M602648200
Submitted on March 21, 2006
Accepted on May 22, 2006
PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum
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