Nr. Murray et Ap. Fields, PHOSPHATIDYLGLYCEROL IS A PHYSIOLOGICAL ACTIVATOR OF NUCLEAR-PROTEIN KINASE-C, The Journal of biological chemistry, 273(19), 1998, pp. 11514-11520
A major mechanism by which protein kinase C (PKC) function is regulate
d is through the selective targeting and activation of individual PKC
isotypes at distinct subcellular locations. PHC beta(II), is selective
ly activated at the nucleus during G(2), phase of cell cycle where it
is required for entry into mitosis. Selective nuclear activation of PK
C beta(II), is conferred by molecular determinants within the carboxyl
-terminal catalytic domain of the kinase (Walker, S. D., Murray, N. R.
, Burns, D. J., and Fields, A. P. (1995) Proc. Natl. Acad. Sci. U.S.A.
92, 9156-9160). We previously described a lipid-like PRC activator in
nuclear membranes, termed nuclear membrane activation factor (NMAF),
that potently stimulates PRC beta(II), activity through interactions i
nvolving this domain (Murray, N. R., Burns, D. J., and Fields, AP. (19
94) J. Biol. Chem. 269, 21385-21390). We have now identified NMAF as p
hosphatidylglycerol (PG), based on several lines of evidence. First, N
MAF cofractionates with PG as a single peak of activity through multip
le chromatographic separations and exhibits phospholipase sensitivity
identical to that of PG. Second, purified PG, but not other phospholip
ids, exhibits dose-dependent NMAF activity. Third, defined molecular s
pecies of PG exhibit different abilities to stimulate PKC beta(II), ac
tivity. 1,2-Dioleoyl-PG possesses significantly higher activity than o
ther PG species, suggesting that both fatty acid side chain compositio
n and the glycerol head group are important determinants for activity.
Fourth, in vitro binding studies demonstrate that PG binds to the car
boxyl-terminal region of PKC beta(II),, the same region we previously
implicated in NMAF-mediated activation of PKC beta(II),. Taken togethe
r, our results indicate that specific molecular species of nuclear PG
function to physiologically regulate PKC beta(II), activity at the nuc
leus.