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J. Biol. Chem. 275 (45): 35617-35623

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Ceramide Directly Activates Protein Kinase C {zeta} to Regulate a Stress-activated Protein Kinase Signaling Complex*

Nicole A. Bourbon, Jong Yun, , and Mark Kester{ddagger}

From the Department of Pharmacology, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033

ABSTRACT Back to Top

Abstract: We have previously shown that interleukin 1 (IL-1)-receptor-generated ceramide induces growth arrest in smooth muscle pericytes by activating an upstream kinase in the stress-activated protein kinase (SAPK) cascade. We now report the mechanism by which ceramide activates the SAPK signaling pathway in human embryonic kidney cells (HEK-293). We demonstrate that ceramide activation of protein kinase C {zeta} (PKC{zeta}) mediates SAPK signal complex formation and subsequent growth suppression. Ceramide directly activates both immunoprecipitated and recombinant human PKC{zeta} in vitro. Additionally, ceramide activates SAPK activity, which is blocked with a dominant-negative mutant of PKC{zeta}. Co-immunoprecipitation studies reveal that ceramide induces the association of SAPK with PKC{zeta}, but not with PKC{varepsilon}. In addition, ceramide treatment induces PKC{zeta} association with phosphorylated SEK and MEKK1, elements of the SAPK signaling complex. The biological role of ceramide to induce cell cycle arrest is mimicked by overexpression of a constitutively active PKC{zeta}. Together, these studies demonstrate that ceramide induces cell cycle arrest by enhancing the ability of PKC{zeta} to form a signaling complex with MEKK1, SEK, and SAPK.

Received for publication August 11, 2000. Revision received August 25, 2000.

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