Pigment Epithelium-derived Factor Receptor (PEDF-R): A Plasma Membrane-linked Phospholipase with PEDF Binding Affinity

  • Preeti Subramanian
  • Patricia M. Notario
  • S. Patricia Becerra
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)


Pigment epithelium-derived factor (PEDF), a multifunctional protein, acts in retinal differentiation, survival and maintenance by interacting with high affinity receptors on the surface of target cells. We have recently identified PEDF-R, a new member of the patatin-like phospholipase domain-containing 2 (PNPLA2) family with characteristics of a PEDF receptor. The PEDF-R sequence reveals a patatin-like phospholipase domain toward its amino-end, and four transmembrane domains interrupted by two extracellular loops and three intracellular regions along its polypeptide sequence. This newly identified protein is present on the surface of retina and RPE cells, and has the expected transmembrane topology. It has specific and high binding affinity for PEDF, and exhibits a potent phospholipase A2 activity that liberates fatty acids. Most importantly, PEDF binding stimulates the enzymatic phospholipase A2 activity of PEDF-R. In summary, PEDF-R is a novel component of the retina that is a phospholipase-linked membrane protein with high affinity for PEDF. The results suggest a molecular pathway by which PEDF ligand/receptor interactions on the cell surface could generate a cellular signal. These conclusions enhance our understanding of the role of PEDF as a neurotrophic survival factor.


Retinal Pigment Epithelium Retinal Pigment Epithelium Cell Extracellular Loop Transmembrane Topology Retinal Pigment Epithelium Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alberdi E, Aymerich MS, Becerra SP (1999) Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons. Evidence for a PEDF receptor. J Biol Chem 274:31605–31612CrossRefPubMedGoogle Scholar
  2. Aymerich MS, Alberdi EM, Martinez A et al (2001) Evidence for pigment epithelium-derived factor receptors in the neural retina. Invest Ophthalmol Vis Sci 42:3287–3293PubMedGoogle Scholar
  3. Barnstable CJ, Tombran-Tink J (2004) Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Prog Retin Eye Res 23:561–577CrossRefPubMedGoogle Scholar
  4. Bazan NG (2005) Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathol 15:159–166CrossRefPubMedGoogle Scholar
  5. Bazan NG, Marcheselli VL, Hu J et al (2005) Pigment epithelium-derived growth factor (PEDF) selectively up-regulates NPD1 synthesis and release through the apical side of human RPE cells in primary cultures. Invest Ophthalmol Vis Sci 46:167Google Scholar
  6. Becerra SP (2006) Focus on Molecules: pigment epithelium-derived factor (PEDF). Exp Eye Res 82:739–740CrossRefPubMedGoogle Scholar
  7. Becerra SP, Fariss RN, Wu YQ et al (2004) Pigment epithelium-derived factor in the monkey retinal pigment epithelium and interphotoreceptor matrix: apical secretion and distribution. Exp Eye Res 78:223–234CrossRefPubMedGoogle Scholar
  8. Bilak MM, Corse AM, Bilak SR et al (1999) Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J Neuropathol Exp Neurol 58:719–728CrossRefPubMedGoogle Scholar
  9. Bouck N (2002) PEDF: anti-angiogenic guardian of ocular function. Trends Mol Med 8:330–334CrossRefPubMedGoogle Scholar
  10. Cao W, Tombran-Tink J, Elias R et al (2001) In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 42:1646–1652PubMedGoogle Scholar
  11. Cayouette M, Smith SB, Becerra SP et al (1999) Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis 6:523–532CrossRefPubMedGoogle Scholar
  12. Chader GJ (2005) Surmountable challenges in translating pigment epithelium-derived factor (PEDF) therapy from animal models to clinical trials for retinal degenerations. Retina (Philadelphia, PA) 25:S29–S30CrossRefPubMedGoogle Scholar
  13. Dawson DW, Volpert OV, Gillis P et al (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248CrossRefPubMedGoogle Scholar
  14. Duh EJ, Yang HS, Haller JA et al (2004) Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: implications for ocular angiogenesis. Am J Ophthalmol 137:668–674PubMedGoogle Scholar
  15. Duh EJ, Yang HS, Suzuma I et al (2002) Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 43:821–829PubMedGoogle Scholar
  16. Hirschberg HJ, Simons JW, Dekker N et al (2001) Cloning, expression, purification and characterization of patatin, a novel phospholipase A. Eur J Biochem 268:5037–5044CrossRefPubMedGoogle Scholar
  17. Holekamp NM, Bouck N, Volpert O (2002) Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol 134:220–227CrossRefPubMedGoogle Scholar
  18. Hubbard T, Andrews D, Caccamo M et al (2005) Ensembl 2005. Nucleic Acids Res 33:D447–D453CrossRefPubMedGoogle Scholar
  19. Jenkins CM, Mancuso DJ, Yan W et al (2004) Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem 279:48968–48975CrossRefPubMedGoogle Scholar
  20. Jimenez-Atienzar M, Cabanes J, Gandia-Herrero F et al (2003) Determination of the phospholipase activity of patatin by a continuous spectrophotometric assay. Lipids 38:677–682CrossRefPubMedGoogle Scholar
  21. Murakami Y, Ikeda Y, Yonemitsu Y et al (2008) Inhibition of nuclear translocation of apoptosis-inducing factor is an essential mechanism of the neuroprotective activity of pigment epithelium-derived factor in a rat model of retinal degeneration. Am J Pathol 173:1326–1338CrossRefPubMedGoogle Scholar
  22. Notari L, Baladron V, Aroca-Aguilar JD et al (2006) Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem 281:38022–38037CrossRefPubMedGoogle Scholar
  23. Ogata N, Matsuoka M, Imaizumi M et al (2004) Decreased levels of pigment epithelium-derived factor in eyes with neuroretinal dystrophic diseases. Am J Ophthalmol 137:1129–1130CrossRefPubMedGoogle Scholar
  24. Perez-Mediavilla LA, Chew C, Campochiaro PA et al (1998) Sequence and expression analysis of bovine pigment epithelium-derived factor. Biochim Biophys Acta 1398:203–214PubMedGoogle Scholar
  25. Rydel TJ, Williams JM, Krieger E et al (2003) The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a Ser-Asp catalytic dyad. Biochemistry 42:6696–6708CrossRefPubMedGoogle Scholar
  26. Singh VK, Chader GJ, Rodriguez IR (1998) Structural and comparative analysis of the mouse gene for pigment epithelium-derived factor (PEDF). Mol Vis 4:7PubMedGoogle Scholar
  27. Smirnova E, Goldberg EB, Makarova KS et al (2006) ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells. EMBO Rep 7:106–113CrossRefPubMedGoogle Scholar
  28. Takita H, Yoneya S, Gehlbach PL et al (2003) Retinal neuroprotection against ischemic injury mediated by intraocular gene transfer of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 44:4497–4504CrossRefPubMedGoogle Scholar
  29. Tombran-Tink J, Chader GG, Johnson LV (1991) PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res 53:411–414CrossRefPubMedGoogle Scholar
  30. Tombran-Tink J, Shivaram SM, Chader GJ et al (1995) Expression, secretion, and age-related downregulation of pigment epithelium-derived factor, a serpin with neurotrophic activity. J Neurosci 15:4992–5003PubMedGoogle Scholar
  31. Wu YQ, Notario V, Chader GJ et al (1995) Identification of pigment epithelium-derived factor in the interphotoreceptor matrix of bovine eyes. Protein Expr Purif 6:447–456CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Preeti Subramanian
    • 1
  • Patricia M. Notario
    • 2
  • S. Patricia Becerra
    • 1
  1. 1.NEI-NIHBethesdaUSA
  2. 2.Georgetown University Medical SchoolWashingtonUSA

Personalised recommendations