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J. Biol. Chem., Vol. 268, Issue 21, 15523-15530, 07, 1993
RT Dobrowsky, C Kamibayashi, MC Mumby and YA Hannun
Ceramide activates a cytosolic protein phosphatase present in rat T9 glioma
cells and rat brain. Ceramide-activated protein phosphatase (CAPP) was
found to share several properties with protein phosphatase 2A (PP2A)
leading to the hypothesis that ceramide may directly activate PP2A. PP2A
was isolated as a heterotrimer (AB'C, AB alpha C), heterodimer (AC), or
free C subunit, and the effect of ceramide on the catalytic activity was
assessed. C2-ceramide, 5-20 microM, activated heterotrimeric PP2A up to
3.5-fold but had no effect on the activity of AC or C. Ceramides possessing
hexanoyl, decanoyl, and myristoyl but not stearoyl acyl chains also
activated heterotrimeric PP2A. Ceramide activation of heterotrimeric PP2A
required the presence of a B subunit since trypsinization or heparin
treatment abolished ceramide activation. Activation of heterotrimeric PP2A
was specific for ceramide because related sphingolipids had no effect.
Moreover, dihydro-C2- ceramide, which lacks the trans double bond in the
sphingoid base, inhibited AB'C activity by > 90% at 10 microM. The
specificity of activation of AB'C and AB alpha C by stereoisomers of
C2-ceramide was found to differ. Whereas activation of AB'C by either
DL-erythro- or threo-C2-ceramide was similar, AB alpha C was activated by
either D- or L-erythro-C2-ceramide but not by the threo isomers. CAPP
isolated from T9 cells was most effectively activated by
D-erythro-C2-ceramide. CAPP was found to possess two peaks of ceramide
activated phosphatase activity. The initial peak of activity was coincident
with the elution of AB'C and was stimulated 1.8-fold by 20 microM
C2-ceramide. A second peak of phosphatase activity was negligible in the
absence of ceramide but was stimulated 5.5-fold by 20 microM C2-ceramide.
These results support the hypothesis that ceramide is a specific lipid
second messenger modulating heterotrimeric PP2A activity.
Ceramide activates heterotrimeric protein phosphatase 2A
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
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