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J. Biol. Chem., Vol. 282, Issue 1, 277-286, January 5, 2007

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Insulin Controls Subcellular Localization and Multisite Phosphorylation of the Phosphatidic Acid Phosphatase, Lipin 1^*

Thurl E. Harris, Todd A. Huffman, An Chi, Jeffrey Shabanowitz, Donald F. Hunt, Anil Kumar, and John C. Lawrence, Jr.¹

From the Departments of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia 22908-0735

Brain, liver, kidney, heart, and skeletal muscle from fatty liver dystrophy (fld/fld) mice, which do not express lipin 1 (lipin), contained much less Mg²⁺-dependent phosphatidic acid phosphatase (PAP) activity than tissues from wild type mice. Lipin harboring the fld^2j (Gly⁸⁴ Arg) mutation exhibited relatively little PAP activity. These results indicate that lipin is a major PAP in vivo and that the loss of PAP activity contributes to the fld phenotype. PAP activity was readily detected in immune complexes of lipin from 3T3-L1 adipocytes, where the protein was found both as a microsomal form and a soluble, more highly phosphorylated, form. Fifteen phosphorylation sites were identified by mass spectrometric analyses. Insulin increased the phosphorylation of multiple sites and promoted a gel shift that was due in part to phosphorylation of Ser¹⁰⁶. In contrast, epinephrine and oleic acid promoted dephosphorylation of lipin. The PAP-specific activity of lipin was not affected by the hormones or by dephosphorylation of lipin with protein phosphatase 1. However, the ratio of soluble to microsomal lipin was markedly increased in response to insulin and decreased in response to epinephrine and oleic acid. The results suggest that insulin and epinephrine control lipin primarily by changing localization rather than intrinsic PAP activity.

Received for publication, October 10, 2006 , and in revised form, November 14, 2006.

^* This work was supported by National Institutes of Health Grants DK52753 and DK28312 (to J. C. L.) and GM37537 (to D. F. H.) and by the University of Virginia Diabetes and Endocrinology Research Center. 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: Dept. of Pharmacology, P.O. Box 800735, 1300 Jefferson Park Ave., Charlottesville, VA 22908-0735. Tel.: 434-924-1584; Fax: 434-982-3878; E-mail: jcl3p{at}virginia.edu.

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