Atypical PKC zeta is activated by ceramide, resulting in coactivation of NF-kappa B/JNK kinase and cell survival

Both protein kinase C (PKC) and ceramide play a critical role in cell signa ling, but the relationship between PKC and ceramide is unclear. Low concent rations of ceramide were observed to transiently stimulate PKC zeta activit y in vitro and in vivo, whereas high doses of ceramide lead to inhibition o f PKC zeta, Inhibition of activity was accompanied by enhanced binding of t he negative regulator, Par4 to PKC zeta, Treatment of PC12 cells with low d oses of ceramide promoted survival in serum-free media and activation of nu clear factor-kappa B, whereas higher doses (>2.5 mu M) resulted in cell dea th. Overexpression of either aPKC isoform, PKC zeta or iota, resulted in en hanced survival of PC12 cells at high doses of ceramide and in ceramidestim ulated Jun N-terminal kinase (JNK), without any apparent effect on mitogen- activated kinase. These findings support a role for ceramide-induced PKC ze ta activity in the control of cell survival signaling via a pathway that al so activates JNK kinase. J. Neurosci. 55:293-302, 1999. (C) 1999Wiley-Liss, Inc.