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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.

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