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Molecular and Cellular Biology, August 2006, p. 5861-5875, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.02403-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Phosphatidylinositol 4,5-Biphosphate and TORC2 Binding Proteins Slm1 and Slm2 Function in Sphingolipid Regulation

Mitsuaki Tabuchi ,^1,, Anjon Audhya,^1,,¶ Ainslie B. Parsons,^2,3 Charles Boone,^2,3 and Scott D. Emr^1*

Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, California 92093-0668,¹ Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada,² Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada³

Received 16 December 2005/ Returned for modification 6 February 2006/ Accepted 8 May 2006

The Stt4 phosphatidylinositol 4-kinase has been shown to generate a pool of phosphatidylinositol 4-phosphate (PI4P) at the plasma membrane, critical for actin cytoskeleton organization and cell viability. To further understand the essential role of Stt4-mediated PI4P production, we performed a genetic screen using the stt4^ts mutation to identify candidate regulators and effectors of PI4P. From this analysis, we identified several genes that have been previously implicated in lipid metabolism. In particular, we observed synthetic lethality when both sphingolipid and PI4P synthesis were modestly diminished. Consistent with these data, we show that the previously characterized phosphoinositide effectors, Slm1 and Slm2, which regulate actin organization, are also necessary for normal sphingolipid metabolism, at least in part through regulation of the calcium/calmodulin-dependent phosphatase calcineurin, which binds directly to both proteins. Additionally, we identify Isc1, an inositol phosphosphingolipid phospholipase C, as an additional target of Slm1 and Slm2 negative regulation. Together, our data suggest that Slm1 and Slm2 define a molecular link between phosphoinositide and sphingolipid signaling and thereby regulate actin cytoskeleton organization.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Molecular Genetics, Field of Developmental Medicine, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.

These authors contributed equally to this work.

^¶ Present address: Ludwig Institute for Cancer Research, La Jolla, CA 92093.

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