PP2A Regulates BCL-2 Phosphorylation and Proteasome-mediated Degradation at the Endoplasmic Reticulum
Lin, Stephen S.
Bassik, Michael C.
Arroyo, Jason D.
Hahn, William C.
Korsmeyer, Stanley J.
Roberts, Thomas M.
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CitationLin, Stephen S., Michael C. Bassik, Heikyung Suh, Mari Nishino, Jason D. Arroyo, William C. Hahn, Stanley J. Korsmeyer, and Thomas M. Roberts. 2006. “PP2A Regulates BCL-2 Phosphorylation and Proteasome-Mediated Degradation at the Endoplasmic Reticulum.” Journal of Biological Chemistry 281 (32): 23003–12. doi:10.1074/jbc.M602648200.
AbstractAnti-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.
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