The neuroprotective and angiogenesis inhibitory serpin, PEDF: new insights into phylogeny, function, and signaling

Tombran-Tink, Joyce

doi:10.2741/1686

Cited by 76 publications

(68 citation statements)

References 89 publications

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“…36 Therefore, the exact mechanisms by which PEDF and its mutants exert their different activities are not clear. We have found that rPEDF binds in a similar affinity to both HUVEC and Y-79 cells (kDa, ϳ5 nM), and this binding is displaced equally well by the different phosphorylation mutants (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Maik-Rachline

Seger

2006

Blood

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The pigment epithelium-derived factor (PEDF) belongs to the family of noninhibitory serpins. Although originally identified in the eye, PEDF is widely expressed in other body regions including the plasma. This factor can act either as a neurotrophic or as an antiangiogenic factor, and we previously showed that the 2 effects of PEDF are regulated through phosphorylation by PKA and CK2. Here, we studied the interplay between the PKA and CK2 phosphorylation of PEDF, and found that a PEDF mutant mimicking the CK2-phosphorylated PEDF cannot be phosphorylated by PKA, while the mutant mimicking the PKA-phosphorylated PEDF is a good CK2 substrate. Using triple mutants that mimic the PKA-and CK2-phosphorylated and nonphosphorylated PEDF, we found that PEDF can induce several distinct cellular activities dependent on its phosphorylation. The mutant mimicking the accumulative PKA plus CK2 phosphorylation exhibited the strongest antiangiogenic and neurotrophic activities, while the mutants mimicking the individual phosphorylation site mutants had either a reduced activity or only one of these activities. Thus, differential phosphorylation induces variable effects of PEDF, and therefore contributes to the complexity of PEDF action. It is likely that the triple phosphomimetic mutant can be used to generate effective antiangiogenic or neurotrophic drugs. IntroductionThe pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitors (serpin) superfamily, but as of today was not found to exhibit inhibitory activity against any proteases. 1,2 It was first isolated based on its ability to convert dividing retinoblastoma cells into differentiated neurons, and thus was characterized as a neurotrophic factor. 1,3 Later, it was shown that besides its neurotrophic functions, PEDF is a potent natural inhibitor of angiogenesis in the eye, 4 where it inhibits stimulatory activity of several strong proangiogenic factors. This antiangiogenic potency has also been shown in several animal models in which PEDF was demonstrated as the factor responsible for the reduction of bloodvessel growth in the eye. [5][6][7][8][9] Although originally discovered in the culture medium of pigment epithelial cells obtained from the fetal human retina, 10 it is clear today that PEDF is expressed not only in the retina, but also at multiple sites in the adult eye, [11][12][13] as well as in the adult human brain, the spinal cord, 14,15 and human plasma. 16 Therefore, it is possible that PEDF has the potential to inhibit angiogenesis throughout the body.It is well established that protein phosphorylation plays a key role in the regulation of most intracellular processes. However, it is becoming increasingly evident that protein kinases can also regulate extracellular processes, as the kinases are present extracellularly as either ectoprotein or exoprotein kinases. 17,18 The ectoprotein kinases are membrane-bound enzymes whose catalytic activities are localized on the extracellular cell surface of a wide variety of cells. The exoprotein k...

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Section: Discussionmentioning

confidence: 99%

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Maik-Rachline

Seger

2006

Blood

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“…Therefore, PEDF was originally thought to be a neurotrophic factor in the retina. Subsequent studies demonstrated that PEDF is an anti-VEGF agent in the retinal vasculature (14). More recent experiments have provided evidence that VEGF secretion across the apical RPE membrane can occur under oxidative stress (30,31).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent experiments have recognized that PEDF is an endogenous antagonist of VEGF (14). In the eye, studies have provided evidence that endothelial quiescence and barrier function is achieved through a balance of VEGF and PEDF (15).…”

Section: Age-related Macular Degeneration (Amd)mentioning

confidence: 99%

“…In endothelial cells, PEDF has also been shown to compete with VEGF for binding at the VEGF-R2 receptor (20). PEDF was found to regulate VEGF expression (20,21) and decrease VEGF receptor phosphorylation (14). A recent study in endothelia has elucidated a novel inhibitory mechanism of VEGF signaling via the PEDF-induced intramembrane proteolysis of VEGF-R1 by ␥-secretase (22).…”

Section: Age-related Macular Degeneration (Amd)mentioning

confidence: 99%

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Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

Ablonczy

Prakasam

Fant

et al. 2009

Journal of Biological Chemistry

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Wet age-related macular degeneration (AMD) attacks the integrity of the retinal pigment epithelium (RPE) barrier system. The pathogenic process was hypothesized to be mediated by vascular endothelial growth factor (VEGF) and antagonized by pigment epithelium-derived factor (PEDF). To dissect these functional interactions, monolayer cultures of RPE cells were established, and changes in transepithelial resistance were evaluated after administration of PEDF, placenta growth factor (VEGF-R1 agonist), and VEGF-E (VEGF-R2 agonist). A recently described mechanism of VEGF inhibition in endothelia required the release of VEGF-R1 intracellular domain by ␥-secretase. To evaluate this pathway in the RPE, cells were pretreated with inhibitors DAPT or LY411575. Processing of VEGF receptors was assessed by Western blot analysis. Administration of VEGF-E rapidly increased RPE permeability, and PEDF inhibited the VEGF-E response dose-dependently. Both ␥-secretase antagonists prevented the inhibitory effects of PEDF. The co-administration of PEDF and VEGF-E depleted the amount of VEGF-R2 in the membrane and increased the amount of VEGF-R2 ectodomain in the media. Therefore, the inhibitory effect of PEDF appears to be mediated via the processing of VEGF-R2 by ␥-secretase. ␥-Secretase generates the amyloid-␤ (A␤) peptide of Alzheimer disease from its precursor (amyloid precursor protein). This peptide is also a component of drusen in dry AMD. The results support the hypothesis that misregulation of ␥-secretase may not only lead to A␤ deposits in dry AMD but can also be damaging to RPE function by blocking the protective effects of PEDF to prevent VEGF from driving the dry to wet AMD transition. Age-related macular degeneration (AMD)2 is often diagnosed by the appearance of subretinal fluid. This fluid causes a local detachment of the retina in the macular area resulting in decreased visual acuity in the center of the visual field (1). The resulting macular edema can lead to complete vision loss (2). Although the excessive fluid mainly comes from capillaries in the inner retina, the removal of subretinal fluid is dependent on the RPE. The maintenance of RPE barrier function is essential for the efficient removal of the fluid (3), and the disruption of the RPE barrier can eventually lead to choroidal neovascularization.Recent clinical studies have shown that intravitreally administered anti-VEGF compounds are effective therapies for choroidal neovascularization (4 -6). Originally, VEGF was described as an endothelial angiogenic and vasopermeability factor. The leakage through the vessels of the inner retina increases in response to VEGF (7,8). However, the release of VEGF also affects RPE function (9 -11). We have recently shown that RPE barrier integrity is modulated by VEGF through apically oriented VEGF-R2 receptors (12). Thus, there is a growing body of evidence that intraocular VEGF can increase the permeability of both the inner and outer bloodretina barriers, contributing to the accumulation of subretinal fluid and macular ed...

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“…12 Although PEDF signalling has not been fully elucidated, inhibition of both nuclear factor kappa-light-chain-enhancer of activated B cells (NFjB) and ERK1/2 pathways abolishes the protective effects of PEDF in cultured RGC. 12,30,36,70 For example, activation of the NFjB pathway induces the expression of BDNF, NGF, Bcl-2, Bcl-x, and superoxide dismutase, 71,72 but PEDF-activated ERK1/2 modulates kinases, phosphatases, transcription factors, and regulators of apoptosis. 73,74 RGC neuritogenesis/axogenesis were stimulated by PEDF and, after combined cAMPþPEDF treatments, neurites/axons grew for greater distances than after PEDF alone.…”

Section: Discussionmentioning

confidence: 99%

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Vigneswara V, Berry M, Logan A, Ahmed Z. Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury. Invest Ophthalmol Vis Sci. 2013;54: 262454: -263354: . DOI: 10.1167 PURPOSE. To investigate neuroprotective and axogenic properties of pigment epitheliumderived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.METHODS. Adult rat retinal cultures were treated with combinations of PBS and PEDF with or without a cell permeable analogue of cAMP, and RGC survival and neurite lengths quantified. The optic nerves of anesthetised rats were also crushed intraorbitally to transect all RGC axons followed by intravitreal injections of either PBS, PEDF, or cAMPþPEDF every 7 days. RGC were back filled with FluoroGold to quantify RGC survival and longitudinal optic nerve sections were stained with GAP43 antibodies to detect regenerating RGC axons.RESULTS. An optimal dose of 2.5 3 10 À5 lg/lL, promoted 65% more RGC survival than controls in vitro, increasing by 4.4-and 5-fold the number of RGC with neurites and the mean neurite length, respectively. Addition of cAMP with or without PEDF did not potentiate RGC survival or the mean number of RGC with neurites, but enhanced RGC neurite length by 1.4-fold, compared with PEDF alone. After optic nerve crush (ONC), PEDF protected RGC from apoptosis and increased the numbers of regenerating RGC axons in the optic nerve by 4.6-and 3.4-fold, respectively when compared with controls. cAMP did not enhance PEDF-induced RGC neuroprotection, but potentiated its neuroregenerative effects by 2-to 3-fold, increasing the number of RGC axons regenerating at 500 and 1000 lm from the lesions site.CONCLUSIONS. This study is the first to demonstrate that PEDF enhances both RGC survival and axon regeneration in vitro and in vivo.Keywords: PEDF, retinal ganglion cells, neuroprotection, axon regeneration, optic nerve R etinal ganglion cells (RGC) rapidly die after axotomy, but are protected by combinatorial treatments with neurotrophic factors (NTF), including brain-derived NTF (BDNF), neurotrophin-3/4 (NT-3/4), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic (GDNF), and basic fibroblast growth factor (FGF2). 1-7 NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration.1-7 Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts. [16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that ...

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The neuroprotective and angiogenesis inhibitory serpin, PEDF: new insights into phylogeny, function, and signaling

Cited by 76 publications

References 89 publications

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

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