Pigment epithelium-derived factor (PEDF) was originally discovered by Joyce Tombran-Tink and Lincoln Johnson in the late 1980s.[8][9] This group was studying human retinal cell development by identifying secreted factors produced by theretinal pigmented epithelium (RPE), a layer of cells that supports the retina. Upon noticing RPE produced a factor that promoted the differentiation of primitive retinal cells into cells of aneuronal phenotype, they set out to determine the identity of the factor. They isolated proteins unique to RPE cells and tested the individual proteins for neurotrophic function, meaning promoting a neuronal phenotype. A neurotrophic protein around 50 kilodaltons (kDa) was identified and temporarily named RPE-54 before being officially termed pigment epithelium-derived factor.
Soon thereafter, the same laboratorysequenced the PEDF protein and compared it to a human fetal eyelibrary.[7] They found that PEDF was a previously uncharacterized protein and a member of theserpin (serine protease inhibitor) family.
Thegene encoding human PEDF was localized to the 17thchromosome at position 17p13.1.[10] The human PEDF gene is around 15.6kb, and themRNA transcript is around 1.5kb.[11] Immediately upstream of the PEDF gene lies a 200bppromoter region with putative binding sites for thetranscription factorsHNF4,CHOP, andUSF. The PEDF gene consists of 8 exons and 7 introns.
The PEDF gene is present in vertebrates from human to fish, but not present in sea squirts, worms, or fruit flies.[11] Sea squirts express several serpin genes, suggesting that the PEDF gene may have arisen from another serpin family member after the evolution of vertebral animals. The gene most homologous to PEDF is its adjacent neighbor on chromosome 17,SerpinF2.
The PEDF protein is a secreted protein of roughly 50kDa size and 418 amino acids in length.[5] The N-terminus contains a leader sequence responsible for protein secretion out of the cell atresidues 1-19. A 34-mer fragment of PEDF (residues 24-57) was shown to haveantiangiogenic properties, and a 44-mer (residues 58-101) was shown to have neurotrophic properties.[12] ABLAST search reveals a putative receptor binding site exists between residues 75-124. Anuclear localization sequence (NLS) exists about 150 amino acids into the protein. The additional molecular weight is partly due to a singleglycosylation site at residue 285.[13] Near the C-terminus at residues 365-390 lies the reactive center loop (RCL) which is normally involved in serine protease inhibitor activity; however, in PEDF this region does not retain the inhibitory function.[5][14]
In 2001, thecrystal structure of PEDF was successfully generated.[15] The PEDF structure includes 3 beta sheets and 10 alpha helices. This discovery demonstrated that PEDF has an asymmetrical charge distribution across the whole protein. One side of the protein is heavily basic and the other side is heavily acidic, leading to a polar 3-D structure. They proposed that the basic side of the protein contains a heparin binding site.
Secreted PEDF binds a receptor on the cell surface termedPEDF-R.[20] PEDF-R hasphospholipase A2 activity which liberates fatty acids from glycerolipids. PEDF enhancesgamma-secretase activity, leading to the cleavage of theVEGF receptor 1 (VEGFR-1) transmembrane domain.[21] This action interferes with VEGF signaling thereby inhibiting angiogenesis.Laminin receptor is also a target for PEDF, and the interaction occurs between residues 24-57 of PEDF, a region known to regulate antiangiogenic function.[22]
PEDF inducesPPAR-gamma expression which in turn inducesp53, a tumor suppressor gene involved incell cycle regulation andapoptosis.[23]Thrombospondin, an antiangiogenic protein, is upregulated by PEDF.[24] PEDF stimulates several other well known signaling cascades such as theRas pathway, theNF-κB pathway, and extrinsic apoptosis cascades.[25]
PEDF has a variety of functions including antiangiogenic, antitumorigenic, and neurotrophic properties.[26]Endothelial cellmigration is inhibited by PEDF.[27] PEDF suppresses retinalneovascularization and endothelialcell proliferation.[28][29] The antiangiogenic residues 24-57 were shown to be sufficient at inhibiting angiogenesis.[30] PEDF is also responsible for apoptosis of endothelial cells either through thep38 MAPK pathway[31] or through theFAS/FASL pathway[32] Antiangiogenic function is also conferred by PEDF through inhibition of bothVEGFR-1[21] andVEGFR-2.[33]
The antitumorigenic effects of PEDF are not only due to inhibition of supporting vasculature, but also due to effects on the cancer cells themselves. PEDF was shown to inhibit cancer cell proliferation and increase apoptosis via the FAS/FASL pathway.[34] VEGF expression by cancer cells is inhibited by PEDF.[35]
PEDF also displays neurotrophic functions. Retinoblastoma cells differentiate into neurons due to the presence of PEDF.[9] Expression of PEDF in the human retina is found at 7.4 weeks of gestation, suggesting it may play a role in retinal neuron differentiation.[36]
PEDF, a protein with many functions, has been suggested to play a clinical role in dry eye, choroidal neovascularization, cardiovascular disease, diabetes, diabetic macular edema, osteogenesis imperfecta and cancer.[37][26][28][30][38][39] As an antiangiogenic protein, PEDF may help suppress unwanted neovascularization of the eye. Molecules that shift the balance towards PEDF and away from VEGF may prove useful tools in both choroidal neovascularization and preventing cancermetastasis formation.[16][40][41]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^abcFilleur S, Nelius T, de Riese W, Kennedy RC (Apr 2009). "Characterization of PEDF: a multi-functional serpin family protein".Journal of Cellular Biochemistry.106 (5):769–75.doi:10.1002/jcb.22072.PMID19180572.S2CID30871963.
^Tombran-Tink J, Johnson LV (Aug 1989). "Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells".Investigative Ophthalmology & Visual Science.30 (8):1700–7.PMID2668219.
^Tombran-Tink J, Pawar H, Swaroop A, Rodriguez I, Chader GJ (Jan 1994). "Localization of the gene for pigment epithelium-derived factor (PEDF) to chromosome 17p13.1 and expression in cultured human retinoblastoma cells".Genomics.19 (2):266–72.doi:10.1006/geno.1994.1057.hdl:2027.42/31831.PMID8188257.
^abYang H, Xu Z, Iuvone PM, Grossniklaus HE (May 2006). "Angiostatin decreases cell migration and vascular endothelium growth factor (VEGF) to pigment epithelium derived factor (PEDF) RNA ratio in vitro and in a murine ocular melanoma model".Molecular Vision.12:511–7.PMID16735992.
^Tombran-Tink J, Barnstable CJ (Aug 2003). "PEDF: a multifaceted neurotrophic factor".Nature Reviews. Neuroscience.4 (8):628–36.doi:10.1038/nrn1176.PMID12894238.S2CID3113843.
^abRychli K, Huber K, Wojta J (Nov 2009). "Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease".Expert Opinion on Therapeutic Targets.13 (11):1295–302.doi:10.1517/14728220903241641.PMID19694500.S2CID12373314.
^Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (Jul 1999). "Pigment epithelium-derived factor: a potent inhibitor of angiogenesis".Science.285 (5425):245–8.doi:10.1126/science.285.5425.245.PMID10398599.
^abMori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, Mori K, Yang HS, Zack DJ, Ettyreddy D, Brough DE, Wei LL, Campochiaro PA (Aug 2001). "Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization".Journal of Cellular Physiology.188 (2):253–63.doi:10.1002/jcp.1114.PMID11424092.S2CID22379964.
^Duh EJ, Yang HS, Suzuma I, Miyagi M, Youngman E, Mori K, Katai M, Yan L, Suzuma K, West K, Davarya S, Tong P, Gehlbach P, Pearlman J, Crabb JW, Aiello LP, Campochiaro PA, Zack DJ (Mar 2002). "Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth".Investigative Ophthalmology & Visual Science.43 (3):821–9.PMID11867604.
^Takenaka K, Yamagishi S, Jinnouchi Y, Nakamura K, Matsui T, Imaizumi T (Nov 2005). "Pigment epithelium-derived factor (PEDF)-induced apoptosis and inhibition of vascular endothelial growth factor (VEGF) expression in MG63 human osteosarcoma cells".Life Sciences.77 (25):3231–41.doi:10.1016/j.lfs.2005.05.048.PMID15985268.
^Karakousis PC, John SK, Behling KC, Surace EM, Smith JE, Hendrickson A, Tang WX, Bennett J, Milam AH (Jun 2001). "Localization of pigment epithelium derived factor (PEDF) in developing and adult human ocular tissues".Molecular Vision.7:154–63.PMID11438800.
^Funatsu H, Yamashita H, Nakamura S, Mimura T, Eguchi S, Noma H, Hori S (Feb 2006). "Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macular edema".Ophthalmology.113 (2):294–301.doi:10.1016/j.ophtha.2005.10.030.PMID16406543.
^Tong JP, Yao YF (Mar 2006). "Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions".Clinical Biochemistry.39 (3):267–76.doi:10.1016/j.clinbiochem.2005.11.013.PMID16409998.
