Sli2 (Ypk1), a Homologue of Mammalian Protein Kinase SGK, Is a Downstream Kinase in the Sphingolipid-Mediated Signaling Pathway of Yeast

doi:10.1128/MCB.20.12.4411-4419.2000

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Molecular and Cellular Biology, June 2000, p. 4411-4419, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Sli2 (Ypk1), a Homologue of Mammalian Protein Kinase SGK, Is a Downstream Kinase in the Sphingolipid-Mediated Signaling Pathway of Yeast

Yidi Sun,¹ Ritsuko Taniguchi,¹ Daisuke Tanoue,² Toshiyuki Yamaji,¹ Hiromu Takematsu,² Kazutoshi Mori,³ Tetsuro Fujita,⁴ Toshisuke Kawasaki,¹ and Yasunori Kozutsumi²^,^*

Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences,¹ Laboratory of Molecular Neurobiology,³ and Laboratory of Membrane Biochemistry and Biophysics,² Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, and Department of Pharmaceutical Manufacturing Chemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka 573-0101,⁴ Japan

Received 28 December 1999/Returned for modification 31 January 2000/Accepted 13 March 2000

ISP-1 is a new type of immunosuppressant, the structure of which is homologous to that of sphingosine. In a previous study,ISP-1 was found to inhibit mammalian serine palmitoyltransferase,the primary enzyme involved in sphingolipid biosynthesis, andto reduce the intracellular pool of sphingolipids. ISP-1 inducesthe apoptosis of cytotoxic T cells, which is triggered by decreasesin the intracellular levels of sphingolipids. In this study, theinhibition of yeast (Saccharomyces cerevisiae) proliferation byISP-1 was observed. This ISP-1-induced growth inhibition was alsotriggered by decreases in the intracellular levels of sphingolipids.In addition, DNA duplication without cytokinesis was detectedin ISP-1-treated yeast cells on flow cytometry analysis. We havecloned multicopy suppressor genes of yeast which overcome thelethal sphingolipid depletion induced by ISP-1. One of these genes,SLI2, is synonymous with YPK1, which encodes a serine/threoninekinase. Kinase-dead mutants of YPK1 did not show any resistanceto ISP-1, leading us to predict that the kinase activity of theYpk1 protein should be essential for this resistance to ISP-1.Ypk1 protein overexpression had no effect on sphingolipid biosynthesisby the yeast. Furthermore, both the phosphorylation and intracellularlocalization of the Ypk1 protein were regulated by the intracellularsphingolipid levels. These data suggest that the Ypk1 proteinis a downstream kinase in the sphingolipid-mediated signalingpathway of yeast. The Ypk1 protein was reported to be a functionalhomologue of the mammalian protein kinase SGK, which is a downstreamkinase of 3-phosphoinositide-dependent kinase 1 (PDK1). PDK1 phosphotidylinositol(PI) is regulated by PI-3,4,5-triphosphate and PI-3,4-bisphosphatethrough the pleckstrin homology (PH) domain. Overexpression ofmammalian SGK also overcomes the sphingolipid depletion in yeast.Taking both the inability to produce PI-3,4,5-triphosphate andPI-3,4-bisphosphate and the lack of a PH domain in the yeast homologueof PDK1, the Pkh1 protein, into account, these findings furthersuggest that yeast may use sphingolipids instead of inositol phospholipidsas lipidmediators.

^* Corresponding author. Mailing address: Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies,Kyoto University, Yoshida-shimoadachi, Kyoto 606-8501, Japan.Phone: 81-75-753-4562. Fax: 81-75-753-4605. E-mail: yasu{at}pharm.kyoto-u.ac.jp.

Molecular and Cellular Biology, June 2000, p. 4411-4419, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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