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J Biol Chem, Vol. 273, Issue 51, 34157-34163, December 18, 1998
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From the Interleukin 3 (IL-3) stimulates the net growth of
murine factor-dependent NSF/N1.H7 and FDC-P1/ER myeloid
cells by stimulating proliferation and suppressing apoptosis. Recently,
we discovered that Bcl2 is phosphorylated at an evolutionarily
conserved serine residue (Ser70) after treatment with
the survival agonists IL-3 or bryostatin 1, a potent activator of
protein kinase (Ito, T., Deng, X., Carr, B., and May, W. S. (1997)
J. Biol. Chem. 272, 11671-11673). In addition, an
intact Ser70 was found to be required for Bcl2's ability
to suppress apoptosis after IL-3 withdrawal or toxic chemotherapy. We
now show that phosphorylation of Bcl2 occurs rapidly after the addition
of agonist to IL-3-deprived cells and can be reversed by the action of
an okadaic acid (OA)-sensitive phosphatase. A role for protein
phosphatase (PP) 2A as the Bcl2 regulatory phosphatase is supported by
several observations: 1) dephosphorylation of Bcl2 is blocked by OA, a potent PP1 and PP2A inhibitor; 2) intracellular PP2A, but not PP1,
co-localizes with Bcl2; 3) the purified PP2Ac catalytic subunit directly dephosphorylates Bcl2 in vitro in an OA-sensitive
manner; 4) the purified PP2Ac catalytic subunit preferentially
dephosphorylates Bcl2 in vitro compared with PP1 and PP2B;
5) reciprocal immunoprecipitation studies indicate a direct interaction
between PP2A and hemagglutinin (HA)-Bcl2; and 6) treatment of
factor-deprived cells with bryostatin 1 dramatically increases the
association between PP2A and Bcl2. Increased association between Bcl2
and PP2A occurs 15 min after agonist stimulation when Bcl2
phosphorylation has peaked and immediately before dephosphorylation. An
agonist-induced increased association of PP2A and Bcl2 fails to occur
in cells expressing the inactive, phosphorylation-negative S70A Bcl2
mutant, which indicates that an intact Ser70 site is
necessary and sufficient for the interaction to occur. Functional
phosphorylation of Bcl2 at Ser70 is proposed to be a
dynamic process regulated by the sequential action of an
agonist-activated Bcl2 kinase and PP2A.
Sealy Center for Oncology and Hematology and
Department of Internal Medicine, University of Texas Medical
Branch, Galveston, Texas 77555-1048 and the § Department of
Pharmacology, University of Texas Southwestern Medical Center, Dallas,
Texas 75235-9041
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