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Vol. 19, Issue 7, 3080-3096, July 2008

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The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7090

Submitted December 27, 2007; Revised April 1, 2008; Accepted May 1, 2008
Monitoring Editor: Adam Linstedt

InCytes from MBC

Phosphoinositides (PIPs) are ubiquitous regulators of signal transduction events in eukaryotic cells. PIPs are degraded by various enzymes, including PIP phosphatases. The integral membrane Sac1 phosphatases represent a major class of such enzymes. The central role of lipid phosphatases in regulating PIP homeostasis notwithstanding, the biological functions of Sac1-phosphatases remain poorly characterized. Herein, we demonstrate that functional ablation of the single murine Sac1 results in preimplantation lethality in the mouse and that Sac1 insufficiencies result in disorganization of mammalian Golgi membranes and mitotic defects characterized by multiple mechanically active spindles. Complementation experiments demonstrate mutant mammalian Sac1 proteins individually defective in either phosphoinositide phosphatase activity, or in recycling of the enzyme from the Golgi system back to the endoplasmic reticulum, are nonfunctional proteins in vivo. The data indicate Sac1 executes an essential household function in mammals that involves organization of both Golgi membranes and mitotic spindles and that both enzymatic activity and endoplasmic reticulum localization are important Sac1 functional properties.

Address correspondence to: Vytas A. Bankaitis (vytas{at}med.unc.edu)

Abbreviations used: BrdU, bromodeoxyuridine; BSA, bovine serum albumin; ER, endoplasmic reticulum; ES, embryonic stem; FACS, fluorescence-activated cell sorting; GAG, glycosaminoglycan; GFP, green fluorescent protein; Ins, inositol; LOF, loss-of-function; MT, microtubule; PBS, phosphate-buffered saline; PIP, phosphoinositide; PITP, phosphatidylinositol transfer protein; PtdIns, phosphatidylinositol; RFP, red fluorescent protein; RT-PCR, reverse transcriptase-polymerase chain reaction; TGN, trans-Golgi network; VSV-G, vesicular stomatitis virus glycoprotein.

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