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

Abstract

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-Iinked 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.

Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R)

“…PEDF-R Is Critical for PEDF Retinal Survival Activity-We and others have shown that rat retinal precursor R28 cells respond to PEDF stimuli, express the Pnpla2 gene, and contain active PEDF-R protein in their membrane extracts (26,35,40,41). To determine if PEDF-R is a functional receptor for the activities of PEDF in these cells, we first corroborated the location of the PEDF-R protein to the R28 cell surface.…”

“…Indeed, PEDF-R exhibits PLA 2 , triglyceride lipase, and acylglycerol transacylase activities (26,34). Moreover, we have shown that PEDF stimulates the PLA 2 activity of the PEDF-R enzyme, resulting in the release of fatty acids from phospholipids (26,35).…”

“…PEDF-R is a member of the PNPLA2 (patatin-like phospholipase domain-containing 2) family and is also known as adipocyte triglyceride lipase, transport secretion protein-2.2, Ca 2ϩ independent phospholipase A2, and desnutrin (32)(33)(34). The structure of the exons of PNPLA2 reflects the proposed domain structure of the protein with three endodomains (L1, L3, and L5) and two ectodomains (L2 and L4) (35). Immunoreactivity of non-permeabilized cells, FACS, antibody capture experiments using antibodies to peptides from intracellular L3 and extracellular L4 domains, and cell surface biotinylation experiments agree with the predicted PEDF-R topology and show that PEDF-R is one of the proteins labeled at the surface of ARPE-19 cells (26).…”

“…The location of PEDF-R in plasma membranes of retina cells (Fig. 5A) (26,35) makes it an excellent target for cell surface interactions with extracellular PEDF to subsequently trigger cell signaling.…”

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

“…In our previous studies, we showed that endometrial cells express Patatin-like phospholipase domain-containing protein 2 (PNPLA2; ref. 22), a PEDF receptor (PEDF-R) that mediates mainly prosurvival activity (24). Another key protein that regulates the anti-angiogenic activity of PEDF is laminin receptor (LR; ref.…”