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J Biol Chem. 1995 May 26;270(21):12808-13.

The dimeric and catalytic subunit forms of protein phosphatase 2A from rat brain are stimulated by C2-ceramide.

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  • 1Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.


Protein phosphatase 2A (PP-2A) is a heterotrimeric enzyme consisting of a catalytic (C) subunit and A and B regulatory subunits. PP-2A is activated by ceramide in vitro suggesting that PP-2A may be a target of this putative second messenger in vivo (Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., and Hannun, Y. A. (1993) J. Biol. Chem. 268, 15523-15530). In this study, sensitivity to ceramide was only observed when the B subunit was present, suggesting that the B subunit was required for ceramide activation. Here we show that dimeric PP-2A, produced from trimeric PP-2A by heparin-agarose-induced dissociation of the B subunit and isolated by preparative native electrophoresis, is activated by ceramide. The catalytic subunit of PP-2A, produced from trimeric PP-2A by freezing and thawing in the presence of 0.2 M beta-mercaptoethanol and isolated by gel filtration, is also activated by ceramide. The trimeric and catalytic subunit forms of PP-2A exhibit a similar dose dependence of activation by ceramide, and are stimulated to a similar extent at ceramide concentrations yielding maximal activation. These findings indicate that neither the A nor the B subunit is required for ceramide stimulation of PP-2A. Together, these results demonstrate that the catalytic subunit contains a ceramide binding site and suggest that efforts to understand the mechanism of activation of PP-2A by ceramide should be focused on this subunit. The discovery that the catalytic subunit contains a ceramide binding site raises the possibility that other members of this serine/threonine phosphatase gene family may contain lipid binding sites and be regulated by ceramide or other lipid second messengers.

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