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MBC in Press, published online ahead of print November 12, 2008
Mol. Biol. Cell 10.1091/mbc.E08-07-0669

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Submitted on July 2, 2008
Revised on October 21, 2008
Accepted on November 3, 2008

Casein Kinase I{gamma}2 Down-regulates Trafficking of Ceramide in the Synthesis of Sphingomyelin

Nario Tomishige,* Keigo Kumagai,*{dagger} Jun Kusuda,{ddagger} Masahiro Nishijima,*{sect} and Kentaro Hanada*

*Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan; {dagger}CREST of Japan Science and Technology Agency, Saitama 332-0012, Japan; {ddagger}Department of Biomedical Resources, National Institute of Biomedical Innovation, Osaka 567-0085, Japan

Monitoring Editor: Howard Riezman

Intracellullar trafficking of lipids is fundamental to membrane biogenesis. For the synthesis of sphingomyelin, ceramide is transported from the endoplasmic reticulum to the Golgi apparatus by the ceramide transfer protein CERT. CERT is phosphorylated by protein kinase D at S132 and subsequently multiple times in a serine-repeat motif, resulting in its inactivation. However, the kinase involved in the multiple phosphorylation remains unclear. We here identify the {gamma}2 isoform of casein kinase I (CKI{gamma}2) as a kinase whose overexpression confers sphingomyelin-directed toxin-resistance to CHO cells. In a transformant stably expressing CKI{gamma}2, CERT was hyperphosphorylated, and the intracellular trafficking of ceramide was retarded, thereby reducing de novo sphingomyelin synthesis. The reduction in the synthesis of sphingomyelin caused by CKI{gamma}2 was reversed by the expression of CERT mutants that are not hyperphosphorylated. Furthermore, CKI{gamma}2 directly phosphorylated CERT in vitro. Among three {gamma} isoforms, only knockdown of {gamma}2 isoform caused drastic changes in the ratio of hypo- to hyper-phosphorylated form of CERT in HeLa cells. These results indicate that CKI{gamma}2 hyperphosphorylates the serine-repeat motif of CERT, thereby inactivating CERT and down-regulating the synthesis of sphingomyelin.

{sect}Present address: National Institute of Health Science, 1–18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.

Address correspondence to: Kentaro Hanada (hanak{at}nih.go.jp)






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