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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1289-1297
HEMATOPOIESIS
Protein phosphatase 2A activates the proapoptotic function
of BAD in interleukin- 3-dependent lymphoid cells by a
mechanism requiring 14-3-3 dissociation
Chi-Wu Chiang,
Gregory Harris,
Cindy Ellig,
Shane C. Masters,
Romesh Subramanian,
Shirish Shenolikar,
Brian E. Wadzinski, and
Elizabeth Yang
From the Departments of Pediatrics, Pharmacology, and
Cell Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University
School of Medicine, Nashville, TN; the Department of Pharmacology,
Emory University School of Medicine, Atlanta, GA; and the Department of
Pharmacology and Cancer Biology, Duke University Medical Center,
Durham, NC.
BAD is a proapoptotic member of the BCL-2 family of proteins,
which play a major role in regulating apoptosis in cytokine-dependent hematopoietic cells. The function of BAD is regulated by reversible phosphorylation. Deprivation of survival factors induces BAD
dephosphorylation, resulting in apoptosis. Serine-threonine
phosphatase activity dephosphorylated BAD in interleukin-3-dependent
FL5.12 lymphoid cells. Inhibition of PP2A activity by treatment of
cells with PP2A-selective inhibitors, okadaic acid and fostriecin,
prevented BAD dephosphorylation in these cells. Conversely, BAD
dephosphorylation was not inhibited by the PP1-selective inhibitor
tautomycin. In cell-free extracts, BAD phosphatase activity was also
inhibited by the PP2A-selective inhibitors okadaic acid and fostriecin, but not by the PP1-specific protein inhibitor I-2. Dissociation of
14-3-3 from BAD was a prerequisite for BAD dephosphorylation in vitro,
suggesting a mechanism by which 14-3-3 can regulate the activation of
the proapoptotic function of BAD in vivo. Significantly, the inhibition
of BAD phosphatase activity rescued cell death induced by survival
factor withdrawal in FL5.12 cells expressing wild-type BAD but not
phosphorylation-defective mutant BAD. These data indicate that PP2A, or
a PP2A-like enzyme, dephosphorylates BAD and, in conjunction with
14-3-3, modulates cytokine-mediated survival.
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