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J Biol Chem, Vol. 274, Issue 30, 21335-21341, July 23, 1999
From the Department of Biochemistry, Medical University of South
Carolina, Charleston, South Carolina 29425
In the present study, we report that phosphatidic
acid (PA) functions as a novel, potent, and selective inhibitor of
protein phosphatase 1 (PP1). The catalytic subunit of PP1
was
inhibited by PA dose-dependently in a noncompetitive manner
with a Ki value of 80 nM. The
inhibition by PA was specific to PP1 as PA failed to inhibit protein
phosphatase 2A (PP2A) or PP2B. Furthermore, PA was the most effective
and potent inhibitor of PP1 compared with other phospholipids. Because
we recently showed that ceramides activated PP1, we next examined the
effects of PA on ceramide stimulation of PP1. PA inhibited both basal
and ceramide-stimulated PP1 activities, and ceramide showed potent and
stereoselective activation of PP1 in the presence of PA. Next, the
effects of PA on ceramide-induced responses were examined. Molt-4 cells
took up PA dose- and time-dependently such that by 1 and
3 h, uptake of PA was 0.37 and 0.65% of total PA added,
respectively. PA at 30 µM and calyculin A at 10 nM (an inhibitor of PP1 and PP2A at low concentrations),
but not okadaic acid at 10 nM (a PP2A inhibitor at low
concentrations) prevented poly(ADP-ribose) polymerase proteolysis induced by C6-ceramide. Moreover, the combination of PA
with okadaic acid prevented retinoblastoma gene product
dephosphorylation induced by C6-ceramide. These data
suggest that PA functions as a specific regulator of PP1 and may
reverse or counteract those effects of ceramide that are mediated by
PP1, such as apoptosis and retinoblastoma gene product dephosphorylation.
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