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Papers In Press, published online ahead of print May 22, 2006
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

Stephen S. Lin, Michael C. Bassik, Heikyung Suh, Mari Nishino, Jason D. Arroyo, William C. Hahn, Stanley J. Korsmeyer, and Thomas M. Roberts

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.


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