Atypical PKC ζ is activated by ceramide, resulting in coactivation of NF-κb/JNK kinase and cell survival

Both protein kinase C (PKC) and ceramide play a critical role in cell signaling, but the relationship between PKC and ceramide is unclear. Low concentrations of ceramide were observed to transiently stimulate PKC ζ activity in vitro and in vivo, whereas high doses of ceramide lead to inhibition of PKC ζ. Inhibition of activity was accompanied by enhanced binding of the negative regulator, Par4 to PKC ζ. Treatment of PC12 cells with low doses of ceramide promoted survival in serum‐free media and activation of nuclear factor‐κB, whereas higher doses (>2.5 μM) resulted in cell death. Overexpression of either aPKC isoform, PKC ζ or ι, resulted in enhanced survival of PC12 cells at high doses of ceramide and in ceramide‐stimulated Jun N‐terminal kinase (JNK), without any apparent effect on mitogen‐activated kinase. These findings support a role for ceramide‐induced PKC ζ activity in the control of cell survival signaling via a pathway that also activates JNK kinase. J. Neurosci. 55:293–302, 1999. © 1999 Wiley‐Liss, Inc.