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J. Biol. Chem., Vol. 281, Issue 14, 9297-9306, April 7, 2006

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Lipid Phosphate Phosphatase-2 Activity Regulates S-phase Entry of the Cell Cycle in Rat2 Fibroblasts^*

From the Signal Transduction Research Group and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Lipid phosphates are potent mediators of cell signaling and control processes including development, cell migration and division, blood vessel formation, wound repair, and tumor progression. Lipid phosphate phosphatases (LPPs) regulate the dephosphorylation of lipid phosphates, thus modulating their signals and producing new bioactive compounds both at the cell surface and in intracellular compartments. Knock-down of endogenous LPP2 in fibroblasts delayed cyclin A accumulation and entry into S-phase of the cell cycle. Conversely, overexpression of LPP2, but not a catalytically inactive mutant, caused premature S-phase entry, accompanied by premature cyclin A accumulation. At high passage, many LPP2 overexpressing cells arrested in G₂/M and the rate of proliferation declined severely. This was accompanied by changes in proteins and lipids characteristic of senescence. Additionally, arrested LPP2 cells contained decreased lysophosphatidate concentrations and increased ceramide. These effects of LPP2 activity were not reproduced by overexpression or knock-down of LPP1 or LPP3. This work identifies a novel and specific role for LPP2 activity and bioactive lipids in regulating cell cycle progression.

Received for publication, October 31, 2005 , and in revised form, January 27, 2006.

^* This work was supported in part by Canadian Institutes of Health Research Grants MOP10504 and MOP49491. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. i.

¹ Recipient of a Graduate Student Research award from the Alberta Heritage Foundation for Medical Research.

² Recipient of Medical Scholar award from the Alberta Heritage Foundation for Medical Research and a New Investigator Award and an Operating Budget grant from the Canadian Institute of Health Research.

³ To whom correspondence should be addressed: 357 Heritage Medical Research Centre, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-2078; Fax: 780-492-3383; E-mail: david.brindley{at}ualberta.ca.

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