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J Biol Chem, Vol. 273, Issue 21, 13119-13128, May 22, 1998
Regulation of Protein Phosphatase 2A Activity by Caspase-3
during Apoptosis
Maxine F.
Santoro ,
Robert R.
Annand ,
Molly M.
Robertson ,
Yun-Wen
Peng ,
Matthew J.
Brady§,
John A.
Mankovich¶,
Maria C.
Hackett¶,
Tariq
Ghayur ,
Gernot
Walter**,
Winnie W.
Wong , and
David A.
Giegel
From the Department of Biochemistry and
§ Department of Cell Biology, Parke-Davis Pharmaceutical
Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, the ¶ Department of Molecular Biology, the
 Department of Biochemistry, and the
Department of Immunology, BASF Bioresearch Corporation,
Worcester, Massachusetts 01605, and the ** Department of Pathology,
University of California at San Diego,
La Jolla, California 92093
Although the available evidence suggests
that whereas the caspase family plays a major role in apoptosis, they
are not the sole stimulators of death. A random yeast two-hybrid screen
of a lymphocyte cDNA library (using caspase-3 as the bait) found an
interaction between caspase-3 and the regulatory subunit A of
protein phosphatase 2A. This protein was found to be a substrate for
caspase-3, but not caspase-1, and could compete effectively against
either a protein or synthetic peptide substrate.
In Jurkat cells induced to undergo apoptosis with anti-Fas antibody,
protein phosphatase 2A (PP2A) activity increased 4.5-fold after 6 h. By 12 h, the regulatory A subunit could no longer be
detected in cell lysates. There was no change in the amount of the
catalytic subunit. The effects on PP2A could be prevented by the
caspase family inhibitors acetyl-Asp-Glu-Val-Asp (DEVD) aldehyde or Ac-DEVD fluoromethyl ketone. The mitogen-activated protein (MAP) kinase pathway is regulated by PP2A. At 12 h after the addition of anti-Fas antibody, a decrease in the amount of the
phosphorylated forms of MAP kinase was observed. Again, this loss of
activated MAP kinase could be prevented by the addition of DEVD-cho or
DEVD-fmk. These data are consistent with a pathway whereby induction of
apoptosis activates caspase-3. This enzyme then cleaves the regulatory
A subunit of PP2A, increasing its activity. These data show that the
activated PP2A will then effect a change in the phosphorylation state
of the cell. These data provide a link between the caspases and signal
transduction pathways.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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