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Am J Physiol Cell Physiol 280: C1403-C1411, 2001;
0363-6143/01 $5.00
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Vol. 280, Issue 6, C1403-C1411, June 2001

Inhibitory actions of ceramide upon PKC-epsilon /ERK interactions

Nicole A. Bourbon1, Jong Yun1, Danielle Berkey1, Yizheng Wang2, and Mark Kester1

1 Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania 17033; and 2 Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A 0R6

We have previously shown that interleukin-1 receptor-generated ceramide induces growth arrest in smooth muscle pericytes by inhibiting an upstream kinase in the extracellular signal-regulated kinase (ERK) cascade. Here, we now report the mechanism by which ceramide inhibits ERK activity. Ceramide renders the human embryonic kidney 293 cells (HEK 293) resistant to the mitogenic actions of growth factors and activators of protein kinase C (PKC). A role for PKC to mediate ceramide inhibition of growth factor-induced ERK activity and mitogenesis is suggested, as exogenous ceramide directly inhibits both immunoprecipitated and recombinant PKC-epsilon activities. To confirm that PKC-epsilon is necessary for ceramide-inhibited ERK activity, HEK 293 cells were transfected with a dominant-negative mutant of PKC-epsilon (Delta PKC-epsilon ). These transfected cells respond to insulin-like growth factor I (IGF-I) with a significantly decreased ERK activity that is not further reduced by ceramide treatment. Coimmunoprecipitation studies reveal that the treatment with IGF-I induces the association of ERK with PKC-epsilon but not with PKC-zeta . Ceramide treatment significantly inhibits the IGF-I-induced PKC-epsilon interaction with bioactive phosphorylated ERK. Ceramide also inhibits IGF-I-induced PKC-epsilon association with Raf-1, an upstream kinase of ERK. Together, these studies demonstrate that ceramide exerts anti-mitogenic actions by limiting the ability of PKC-epsilon to form a signaling complex with Raf-1 and ERK.

protein kinase C; extracelular signal-regulated kinase; mitogen-activated protein kinase; ceramide; Raf-1


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