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J. Biol. Chem., Vol. 281, Issue 49, 38022-38037, December 8, 2006

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Identification of a Lipase-linked Cell Membrane Receptor for Pigment Epithelium-derived Factor^*

Luigi Notari, Victoriano Baladron^¶, J. Daniel Aroca-Aguilar^¶1, Natalia Balko, Raul Heredia, Christina Meyer, Patricia M. Notario^||, Senthil Saravanamuthu, Maria-Luisa Nueda^¶1, Francisco Sanchez-Sanchez^¶, Julio Escribano^¶2, Jorge Laborda^¶2, and S. Patricia Becerra²³

From the National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, the Food and Drug Administration, Bethesda, Maryland 20892, ^¶School of Medicine/Centro Regional de Investigaciones Biomédicas, University of Castilla-La Mancha, Albacete 02071, Spain, and ^||Georgetown University, Washington, D. C. 20057

Pigment epithelium-derived factor (PEDF) is an extracellular multifunctional protein belonging to the serpin superfamily with demonstrable neurotrophic, gliastatic, neuronotrophic, antiangiogenic, and antitumorigenic properties. We have previously provided biochemical evidence for high affinity PEDF-binding sites and proteins in plasma membranes of retina, retinoblastoma, and CNS cells. This study was designed to reveal a receptor involved in the biological activities of PEDF. Using a yeast two-hybrid screening, we identified a novel gene from pigment epithelium of the human retina that codes for a PEDF-binding partner, which we term PEDF-R. The derived polypeptide has putative transmembrane, intracellular and extracellular regions, and a phospholipase domain. Recently, PEDF-R (TTS-2.2/independent phospholipase A₂ (PLA₂) and mouse desnutrin/ATGL) has been described in adipose cells as a member of the new calcium-independent PLA₂/nutrin/patatin-like phospholipase domain-containing 2 (PNPLA2) family that possesses triglyceride lipase and acylglycerol transacylase activities. Here we describe the PEDF-R gene expression in the retina and its heterologous expression by bacterial and eukaryotic systems, and we demonstrate that its protein product has specific and high binding affinity for PEDF, has a potent phospholipase A₂ activity that liberates fatty acids, and is associated with eukaryotic cell membranes. Most importantly, PEDF binding stimulates the enzymatic phospholipase A₂ activity of PEDF-R. In conclusion, we have identified a novel PEDF-R gene in the retina for a phospholipase-linked membrane protein with high affinity for PEDF, suggesting a molecular pathway by which ligand/receptor interaction on the cell surface could generate a cellular signal.

Received for publication, January 13, 2006 , and in revised form, October 5, 2006.

^* This work was supported in part by the Intramural Research Program of the NEI, National Institutes of Health, by research grants from the "Universidad de Castilla-La Mancha," and by Grant SAF2002-03086 from the "Ministerio de Ciencia y Tecnologia," Spain. 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 Materials and Methods, Table S1, and Figs. S1-S4.

¹ Recipient of a fellowship from the "Consejeria de Sanidad de la Junta de Comunidades de Castilla-La Mancha."

² These authors should be considered as senior authors for this work.

³ To whom correspondence should be addressed: NEI, National Institutes of Health, Bldg. 7, Rm. 304, 7 Memorial Dr., MSC 0706, Bethesda, MD 20892-0706. Tel.: 301-496-6514; Fax: 301-451-5420; E-mail: becerrap{at}nei.nih.gov.

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