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J. Biol. Chem., Vol. 280, Issue 18, 18087-18094, May 6, 2005

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Disturbance of Sphingolipid Biosynthesis Abrogates the Signaling of Mss4, Phosphatidylinositol-4-phosphate 5-Kinase, in Yeast^*

Takafumi Kobayashi, Hiromu Takematsu¶, Toshiyuki Yamaji||, Shinsuke Hiramoto**, and Yasunori Kozutsumi¶**

From the Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Yoshida Shimoadachi, Sakyo-ku, Kyoto 606-8501, the ^**Supra-biomolecular System Research Group, Frontier Research System, RIKEN, and ^¶CREST, JST, Kawaguchi, Saitama 332-0012, Japan

The functional relationships between phosphoinositides and sphingolipids have not been well characterized to date. ISP-1/myriocin is a potent inhibitor of sphingolipid biosynthesis and induces severe growth defects in eukaryotic cells because of the sphingolipid deprivation. We characterized a novel multicopy suppressor gene of ISP-1-mediated cell death in yeast, MSS4. MSS4 encodes a phosphatidylinositol-4-phosphate 5-kinase that synthesizes phosphatidylinositol (4,5)-bisphosphate (PI4,5P₂). We demonstrate here that ISP-1 treatment of yeast causes defects both in the activity and subcellular localization of Mss4. The effect of the Mss4 defect on the downstream signaling was examined, because interaction between the Mss4 product, PI4,5P₂, and the pleckstrin-homology domain of Rom2 mediates recruitment of Rom2 to the membrane, which is the crucial step for subsequent Rho1/2 activation. Indeed, failure of Rom2 recruitment was observed in ISP-1-treated cells as well as in csg2-deleted cells, which have reduced mannosylated inositolphosphorylceramide. These data suggested that proper sphingolipids are required for the signaling pathway involving Mss4.

Received for publication, December 16, 2004 , and in revised form, February 28, 2005.

^* This work was supported in part by Grants-in-aid for Scientific Research 13470488 (to Y. K.) and 13877373 (to Y. K.) from the Japan Society for the Promotion of Science, Grants-in-aid for Scientific Research on Priority Areas 12140202 (to Y. K.) from the Ministry of Education, Culture, Sports and Technology, CREST, and RIKEN. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the 21st Century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology.

^|| Present address: Dept. of Anatomy, University of California, San Francisco, CA 94143.

To whom correspondence should be addressed. Tel.: 81-75-753-7684; Fax: 81-75-753-7686; E-mail: yasu{at}pharm.kyoto-u.ac.jp.

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