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J. Biol. Chem., Vol. 281, Issue 32, 23003-23012, August 11, 2006

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PP2A Regulates BCL-2 Phosphorylation and Proteasome-mediated Degradation at the Endoplasmic Reticulum^*

Stephen S. Lin, Supported by a fellowship from the Leukemia and Lymphoma Society¹, Michael C. Bassik, Heikyung Suh, Mari Nishino, Jason D. Arroyo², William C. Hahn, Stanley J. Korsmeyer, and Thomas M. Roberts^¶3

From the Howard Hughes Medical Institute, Department of Cancer Immunology and AIDS, Department of Medical Oncology, and ^¶Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115

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.

Received for publication, March 21, 2006

^* This work was supported in part by National Institutes of Health Grants P01 CA92625 and R01 CA50239 (to S. J. K.) and by P01 CA050661 (to T. M. R. and W. C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

² Supported by a predoctoral fellowship from the Howard Hughes Medical Institute.

¹ To whom correspondence may be addressed. E-mail: stephen_lin{at}dfci.harvard.edu. ³ To whom correspondence may be addressed. Tel.: 617-632-3049; Fax: 617-632-4770; E-mail: thomas_roberts{at}dfci.harvard.edu.

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