Glycosaminoglycans in human retinoblastoma cells: Heparan sulfate, a modulator of the pigment epithelium-derived factor-receptor interactions

Alberdi, Elena; Weldon, John E.; Becerra, S. Patricia

doi:10.1186/1471-2091-4-1

Cited by 30 publications

(19 citation statements)

References 35 publications

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“…It has been proposed previously that this activity can be regulated by the binding of PEDF to interaction partners in the extracellular matrix (24). This was further substantiated by the finding that the binding of PEDF to a cell surface receptor could be enhanced by the presence of heparan sulfate (14). Here we show that PEDF is indeed a flexible protein that adopts a different structure upon binding of heparin.…”

supporting

confidence: 61%

“…The absence of any detectable change in intrinsic tryptophan fluorescence by the addition of heparin or the absence NaCl supports the notion that the change observed by limited digestion is subtle and local. However, it is likely that this structural perturbation supports the interaction between PEDF and a cell surface receptor, as suggested by Alberdi et al (14). The finding that low ionic strength induces a similar structural change is not clear.…”

mentioning

confidence: 45%

“…The binding of PEDF to a receptor on the cell surface of retinoblasoma Y-79 cells is significantly improved by the presence of heparin (14). It has been suggested that the mechanism of enhanced receptor binding involves a structural change of PEDF (14).…”

Section: Discussionmentioning

confidence: 94%

“…It has been suggested that the mechanism of enhanced receptor binding involves a structural change of PEDF (14). In this study, we have employed biochemical and biophysical methods to investigate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…The basic region interacts with glycosaminoglycans (12,13). Interestingly, the binding of PEDF to an unidentified receptor on Y-79 retinoblastoma cells is mediated by heparin (14). It has been speculated that heparin functions as a co-factor or induces a conformational change exposing regions involved in the receptor binding.…”

mentioning

confidence: 99%

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Heparin Binding Induces a Conformational Change in Pigment Epithelium-derived Factor

Valnickova

Petersen

Nielsen

et al. 2007

Journal of Biological Chemistry

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Pigment epithelium-derived factor (PEDF) is a noninhibitory serpin found in plasma and in the extracellular space. The protein is involved in different biological processes including cell differentiation and survival. In addition, it is a potent inhibitor of angiogenesis. The function is likely associated with binding to cell surface receptors in a heparin-dependent way (Alberdi, E. M., Weldon, J. E., and Becerra, S. P. (2003) BMC Biochem. 4, 1). We have investigated the structural basis for this observation and show that heparin induces a conformational change in the vicinity of Lys 178 . This structural change was evident both when binding to intact heparin and specific heparin-derived oligosaccharides at physiological conditions or simply when exposing PEDF to low ionic strength. Binding to other glycosaminoglycans, heparin-derived oligosaccharides smaller than hexadecasaccharides (dp16), or type I collagen did not affect the structure of PEDF. The conformational change is likely to expose the epitope involved in binding to the receptor and thus regulates the interactions with cell surface receptors.

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supporting

confidence: 61%

mentioning

confidence: 45%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Heparin Binding Induces a Conformational Change in Pigment Epithelium-derived Factor

Valnickova

Petersen

Nielsen

et al. 2007

Journal of Biological Chemistry

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Acidic Fibroblast Growth Factor (FGF-1) and FGF Receptor 1 Signaling in Human Y79 Retinoblastoma

Siffroi-Fernandez

Cinaroglu²,

Fuhrmann-Panfalone³

et al. 2005

Arch Ophthalmol

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Objectives: Fibroblast growth factors (FGFs) represent potent effectors and play essential roles in both normal development and many pathological processes. Little is known about their possible implication in retinoblastoma growth. We sought to examine FGF high-and lowaffinity receptor (FGFR) expression, activation of FGFR1 by acidic FGF (FGF-1), and proliferative effects on Y79 cells. Methods: Expression of FGFR1 to FGFR4 was screened in Y79 cells by means of immunochemical and reverse transcriptase polymerase chain reaction techniques. Tyrosine phosphorylation of FGFR1 induced by FGF was examined by immunoprecipitation after stimulation with FGF-1 in the presence or absence of heparin. Retinoblastoma proliferation was monitored by radiolabeled thymidine incorporation or a vital dye-based assay, after addition of FGF-1 with or without inclusion of a specific FGFR1 neutralizing antibody or FGFR1 antisense oligonucleotides. Low-affinity heparan sulfate proteoglycan coreceptors were blocked through sodium chlorate or heparinase treatment of Y79 cells. Results: Y79 retinoblastoma expressed all 4 FGFRs, at both the protein and messenger RNA levels. The FGFR1 was differentially phosphorylated in a time-and heparindependent manner by FGF-1. Proliferation of Y79 cells induced by FGF-1 was entirely mediated by FGFR1, since inclusion of specific neutralizing antibodies or antisense oligonucleotides completely prevented tumor cell multiplication. Finally, FGF-1-induced proliferation was dependent on the presence and sulfation of heparan sulfate proteoglycan. Conclusions: Y79 retinoblastoma expresses all 4 FGFRs, but FGFR1 activation entirely accounts for FGF-1-driven cell proliferation. Clinical Relevance: These studies demonstrate a role for the FGF-1/FGFR1 pathway in retinoblastoma proliferation, and may contribute to developing therapeutic strategies to limit retinoblastoma growth.

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Pigment epithelium-derived factor is differentially expressed in peripheral neuropathies

Conti¹,

Ricchiuto²,

Iannaccone³

et al. 2005

Proteomics

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Peripheral neuropathies are characterized by asymmetrical slowly progressive weakness with no upper motor neuron signs, and can occur either with or without pain. Due to poor knowledge of the disease mechanisms, available pain treatment is very limited. Because of the difficulties and invasiveness involved when performing direct analysis on peripheral and CNS, pathological markers can be searched for in the cerebrospinal fluid (CSF) as an alternative. To investigate pain mechanisms in peripheral neuropathy and find diagnostic markers, CSF samples were analyzed by a differential expression proteomic approach. We studied CSF from: neuropathic patients with pain (PN), without pain (NPN) and healthy controls (CN). 2-DE analysis showed ten protein spots differentially expressed, and six of these were identified by MS. In NPN patients we found an expression level decrease of three pigment epithelium-derived factor (PEDF) protein isoforms. Immunoblot with a specific antibody revealed the presence of additional PEDF isoforms not highlighted by differential expression analysis. Fucose residues on the oligosaccharide chain were found only in the isoforms down regulated in NPN patients. Considered as PEDF has important neurobiological effects, it might be considered an interesting pathology marker.

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Glycosaminoglycans in human retinoblastoma cells: Heparan sulfate, a modulator of the pigment epithelium-derived factor-receptor interactions

Cited by 30 publications

References 35 publications

Heparin Binding Induces a Conformational Change in Pigment Epithelium-derived Factor

Heparin Binding Induces a Conformational Change in Pigment Epithelium-derived Factor

Acidic Fibroblast Growth Factor (FGF-1) and FGF Receptor 1 Signaling in Human Y79 Retinoblastoma

Pigment epithelium-derived factor is differentially expressed in peripheral neuropathies

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