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J. Biol. Chem., Vol. 281, Issue 45, 34537-34548, November 10, 2006

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Control of Phospholipid Synthesis by Phosphorylation of the Yeast Lipin Pah1p/Smp2p Mg²⁺-dependent Phosphatidate Phosphatase^*

Laura O'Hara, Gil-Soo Han, Sew Peak-Chew^¶, Neil Grimsey, George M. Carman, and Symeon Siniossoglou¹

From the Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, CB2 2XY Cambridge, United Kingdom, Department of Food Science, Cook College, New Jersey Agricultural Experiment Station, Rutgers University, New Brunswick, New Jersey 08901, and ^¶Medical Research Council Laboratory of Molecular Biology, Hills Road, CB2 2QH Cambridge, United Kingdom

Phosphorylation of the conserved lipin Pah1p/Smp2p in Saccharomyces cerevisiae was previously shown to control transcription of phospholipid biosynthetic genes and nuclear structure by regulating the amount of membrane present at the nuclear envelope (Santos-Rosa, H., Leung, J., Grimsey, N., Peak-Chew, S., and Siniossoglou, S. (2005) EMBO J. 24, 1931-1941). A recent report identified Pah1p as a Mg²⁺-dependent phosphatidate (PA) phosphatase that regulates de novo lipid synthesis (Han G.-S., Wu, W. I., and Carman, G. M. (2006) J. Biol. Chem. 281, 9210-9218). In this work we use a combination of mass spectrometry and systematic mutagenesis to identify seven Ser/Thr-Pro motifs within Pah1p that are phosphorylated in vivo. We show that phosphorylation on these sites is required for the efficient transcriptional derepression of key enzymes involved in phospholipid biosynthesis. The phosphorylation-deficient Pah1p exhibits higher PA phosphatase-specific activity than the wild-type Pah1p, indicating that phosphorylation of Pah1p controls PA production. Opi1p is a transcriptional repressor of phospholipid biosynthetic genes, responding to PA levels. Genetic analysis suggests that Pah1p regulates transcription of these genes through both Opi1p-dependent and -independent mechanisms. We also provide evidence that derepression of phospholipid biosynthetic genes is not sufficient to induce the nuclear membrane expansion shown in the pah1 cells.

Received for publication, July 13, 2006 , and in revised form, September 5, 2006.

^* This work was supported by a Wellcome Trust Career Development Fellowship in Basic Biomedical Science (to S. S.) and by United States Public Health Service, National Institutes of Health Grant GM-28140 (to G. M. C.). 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.

¹ To whom correspondence should be addressed: CIMR, Wellcome Trust/MRC Bldg., Hills Rd. CB2 2XY, Cambridge UK. E-mail: ss560{at}cam.ac.uk.

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