Mw. Wooten et al., MODULATION OF ZETA-PROTEIN KINASE-C BY CYCLIC-AMP IN PC12 CELLS OCCURS THROUGH PHOSPHORYLATION BY PROTEIN-KINASE-A, Journal of neurochemistry, 67(3), 1996, pp. 1023-1031
Although cyclic AMP (cAMP) has been reported to cross talk with the pr
otein kinase C (PKC) system, effects of elevated intracellular cAMP on
the activities of specific PKC isoforms have not been studied. We rep
ort findings from a permeabilized cell assay that was used to examine
changes in the activity of the atypical PKC isoforms brought about by
exposure of PC12 cells to agents that elevate intracellular cAMP. We f
ound that increases in intracellular cAMP led to rapid stimulation of
atypical PKC activity, 40-70% above control, for a sustained period of
lime, a response that occurred independent of the phorbol 12-myristat
e 13-acetate (PMA)sensitive PKC isoforms. Changes in intracellular cAM
P levels resulted in a dose-dependent redistribution of zeta-PKC to th
e cytoplasm with a concomitant increase in the phosphorylation state o
f the enzyme. Incubation of purified zeta-PKC with increasing concentr
ations of PKA likewise caused a twofold increase in the phosphorylatio
n state of zeta-PKC. In contrast to the positive effect that PKA-media
ted phosphorylation had on the activity of zeta-PKC, the enzyme displa
yed reduced binding to ras when phosphorylated. Taken together, these
findings are consistent with the hypothesis that protein phosphorylati
on of PKC acts as a positive effector of its enzyme activity and may s
erve as a negative modulator for interaction with other proteins.