Phosphatidylglycerol is a physiologic activator of nuclear protein kinase C

A major mechanism by which protein kinase C (PKC) function is regulated is through the selective targeting and activation of individual PKC isotypes at distinct subcellular locations. PHC beta(II), is selectively activated at the nucleus during G(2), phase of cell cycle where it is required for entry into mitosis. Selective nuclear activation of PKC 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 involving this domain (Murray, N. R., Burns, D. J., and Fields, AP. (1994) J. Biol. Chem. 269, 21385-21390). We have now identified NMAF as phosphatidylglycerol (PG), based on several lines of evidence. First, NMAF cofractionates with PG as a single peak of activity through multiple chromatographic separations and exhibits phospholipase sensitivity identical to that of PG. Second, purified PG, but not other phospholipids, exhibits dose-dependent NMAF activity. Third, defined molecular species of PG exhibit different abilities to stimulate PKC beta(II), activity. 1,2-Dioleoyl-PG possesses significantly higher activity than other PG species, suggesting that both fatty acid side chain composition and the glycerol head group are important determinants for activity. Fourth, in vitro binding studies demonstrate that PG binds to the carboxyl-terminal region of PKC beta(II),, the same region we previously implicated in NMAF-mediated activation of PKC beta(II),. Taken together, our results indicate that specific molecular species of nuclear PG function to physiologically regulate PKC beta(II), activity at the nucleus.