PKR Regulates B56 alpha-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Kul B. Karanjeet (Creator)

Svitlana M. Kurinna (Creator)

Alberto M. Martelli (Creator)

James A. McCubrey (Creator)

Peter P. Ruvolo (Creator)

Vivian R. Ruvolo (Creator)

Todd F. Schuster (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Protein phosphatase 2A (PP2A) is a heterotrimer comprising catalytic scaffold and regulatory (B) subunits. There are at least 21 B subunit family members. Thus PP2A is actually a family of enzymes defined by which B subunit is used. The B56 family member B56 is a phosphoprotein that regulates dephosphorylation of BCL2. The stress kinase PKR has been shown to phosphorylate B56 at serine 28 in vitro but it has been unclear how PKRmight regulate the BCL2 phosphatase. In the present study PKR regulation of B56 in REH cells was examined because these cells exhibit robust BCL2 phosphatase activity. PKR was found to be basally active in REH cells as would be predicted if the kinase supports B56 -mediated dephosphorylation of BCL2. Suppression of PKR promoted BCL2 phosphorylation with concomitant loss of B56 phosphorylation at serine 28 and inhibition of mitochondrial PP2A activity. PKR supports stress signaling in REH cells as suppression of PKR promoted chemoresistance to etoposide. Suppression of PKR promoted B56 proteolysis which could be blocked by a proteasome inhibitor. However the mechanism by which PKR supports B56 protein does not involve PKR-mediated phosphorylation of the B subunit at serine 28 but may involve eIF2 activation of AKT. Phosphorylation of serine 28 by PKR promotes mitochondrial localization of B56 because wild-type but not mutant S28A B56 promoted mitochondrial PP2A activity. Cells expressing wildtype B56 but not S28A B56 were sensitized to etoposide. These results suggest that PKR regulates B56 -mediated PP2A signaling in REH cells. Originally published Journal of Biological Chemistry Vol. 283 No. 51 Dec 2008

Additional Information

Publication

Other

Journal of Biological Chemistry. 283:51(December 2009) p. 35474-35485.

Language: English

Date: 2011

Keywords

protein phosphatase 2A, B56 alpha, dephosphorylation

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