scholarly journals Comparison of the Interactions of Different Growth Factors and Glycosaminoglycans

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3360 ◽  
Author(s):  
Fuming Zhang ◽  
Lanhong Zheng ◽  
Shuihong Cheng ◽  
Yanfei Peng ◽  
Li Fu ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Transforming Growth Factor ◽  
Keratan Sulfate ◽  
Heparin Binding ◽  
Chip Surface ◽  
High Affinity ◽  
Sulfo Groups

Most growth factors are naturally occurring proteins, which are signaling molecules implicated in cellular multiple functions such as proliferation, migration and differentiation under patho/physiological conditions by interacting with cell surface receptors and other ligands in the extracellular microenvironment. Many of the growth factors are heparin-binding proteins (HBPs) that have a high affinity for cell surface heparan sulfate proteoglycans (HSPG). In the present study, we report the binding kinetics and affinity of heparin interacting with different growth factors, including fibroblast growth factor (FGF) 2,7,10, hepatocyte growth factor (HGF) and transforming growth factor (TGF β-1), using a heparin chip. Surface plasmon resonance studies revealed that all the tested growth factors bind to heparin with high affinity (with KD ranging from ~0.1 to 59 nM) and all the interactions are oligosaccharide size dependent except those involving TGF β-1. These heparin-binding growth factors also interact with other glycosaminoglycans (GAGs), as well as various chemically modified heparins. Other GAGs, including heparan sulfate, chondroitin sulfates A, B, C, D, E and keratan sulfate, showed different inhibition activities for the growth factor-heparin interactions. FGF2, FGF7, FGF10 and HGF bind heparin but the 2-O-sulfo and 6-O-sulfo groups on heparin have less impact on these interactions than do the N-sulfo groups. All the three sulfo groups (N-, 2-O and 6-O) on heparin are important for TGFβ-1-heparin interaction.

Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1997-2005 ◽  
Author(s):  
B.C. Paria ◽  
K. Elenius ◽  
M. Klagsbrun ◽  
S.K. Dey
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Heparan Sulfate Proteoglycans ◽  
Receptor Expression ◽  
Luminal Epithelium ◽  
Apical Surface ◽  
Heparin Binding ◽  
High Affinity ◽  
Blastocyst Implantation

Blastocyst implantation requires molecular and cellular interactions between the uterine luminal epithelium and blastocyst trophectoderm. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) is induced in the mouse luminal epithelium solely at the site of blastocyst apposition at 16:00 hours on day 4 of pregnancy prior to the attachment reaction (22:00-23:00 hours), and that HB-EGF promotes blastocyst growth, zona-hatching and trophoblast outgrowth. To delineate which EGF receptors participate in blastocyst activation, the toxicity of chimeric toxins composed of HB-EGF or TGF-(α) coupled to Pseudomonas exotoxin (PE) were used as measures of receptor expression. TGF-(α) or HB-EGF binds to EGF-receptor (ErbB1), while HB-EGF, in addition, binds to ErbB4. The results indicate that ErbB1 is inefficient in mediating TGF-(α)-PE or HB-EGF-PE toxicity as follows: (i) TGF-(α)-PE was relatively inferior in killing blastocysts, 100-fold less than HB-EGF-PE, (ii) analysis of blastocysts isolated from cross-bred egfr+/− mice demonstrated that HB-EGF-PE, but not TGF-(α)-PE, killed egfr−/− blastocysts, and (iii) blastocysts that survived TGF-(α)-PE were nevertheless killed by HB-EGF-PE. HB-EGF-PE toxicity was partially mediated by cell surface heparan sulfate proteoglycans (HSPG), since a peptide corresponding to the heparin-binding domain of HB-EGF as well as heparitinase treatment protected the blastocysts from the toxic effects of HB-EGF-PE by about 40%. ErbB4 is a candidate for being an HB-EGF-responsive receptor since RT-PCR analysis demonstrated that day 4 mouse blastocysts express two different erbB4 isoforms and immunostaining with anti-ErbB4 antibodies confirmed that ErbB4 protein is expressed at the apical surface of the trophectoderm cells. It is concluded that (i) HB-EGF interacts with the blastocyst cell surface via high-affinity receptors other than ErbB1, (ii) the HB-EGF interaction with high-affinity blastocysts receptors is regulated by heparan sulfate, and (iii) ErbB4 is a candidate for being a high-affinity receptor for HB-EGF on the surface of implantation-competent blastocysts.

scholarly journals Extracellular Matrix and Cytokines: A Functional Unit

2000 ◽  
Vol 7 (2-4) ◽  
pp. 89-101 ◽  
Author(s):  
Elke Schönherr ◽  
Heinz-JüRgen Hausser
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Heparan Sulfate ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Heparin Binding ◽  
Cytokine Network ◽  
Surface Receptors ◽  
Core Proteins ◽  
The Matrix

The extracellular matrix (ECM) as well as soluble mediators like cytokines can influence the behavior of cells in very distinct as well as cooperative ways. One group of ECM molecules which shows an especially broad cooperativety with cytokines and growth factors are the proteoglycans. Proteoglycans can interact with their core proteins as well as their glycosaminoglycan chains with cytokines. These interactions can modify the binding of cytokines to their cell surface receptors or they can lead to the storage of the soluble factors in the matrix. Proteoglycans themselves may even have cytokine activity. In this review we describe different proteoglycans and their interactions and relationships with cytokines and we discuss in more detail the extracellular regulation of the activity of transforming growth factor-β (TGF-β) by proteoglycans and other ECM molecules. In the third part the interaction of heparan sulfate chains with fibroblast growth factor-2 (FGF-2, basic FGF) as a prototype example for the interaction of heparin-binding cytokines with heparan sulfate proteoglycans is presented to illustrate the different levels of mutual dependence of the cytokine network and the ECM.

174 EPIDERMAL GROWTH FACTORS AND CALBINDIN-D9k GENE EXPRESSIONS DURING PREGANCY IN THE PORCINE UTERUS

2008 ◽  
Vol 20 (1) ◽  
pp. 167
Author(s):  
Y.-J. Kim ◽  
E.-M. Jung ◽  
G.-S. Lee ◽  
S.-H. Hyun ◽  
E.-B. Jeung
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Expression Patterns ◽  
Negative Control ◽  
Heparin Binding ◽  
Gene Expressions ◽  
Calbindin D9k ◽  
Genes Encoding ◽  
Epidermal Growth

To stably maintain pregnancy, several genes are expressed in the uterus. In particular, the endometrial expression of genes encoding growth factors appears to play a key role in maternal–fetal communication. Previous studies have characterized the endometrial expression kinetics of the genes encoding epidermal growth factor (EGF), its receptor (EGFR), transforming growth factor-alpha (TGF-α), amphiregulin (Areg), heparin-binding (Hb) EGF, and calbindin-D9k (CaBP-9k) in the pig during implantation. Here, we further characterized the expression patterns of these molecules during the entire porcine pregnancy. Porcine (n = 3 per PD) were collected at pregnancy days (PD) 12, 15, 30, 60, 90, and 110 and subjected to semi-quantitative RT-PCR. The data were analyzed with a nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett's test for multiple comparisons to the negative control. EGF and EGFR showed similar expression patterns, being highly expressed around implantation time and then disappearing. TGF-α and Areg expression levels rose steadily until they peaked at PD30, after which they gradually decreased to PD12 levels. The Areg mRNA expression pattern was confirmed by real-time PCR, and similar Areg protein expression patterns were observed. Immunohistochemical analysis of PD60 uteri revealed Areg in the glandular and luminal epithelial cells. Hb-EGF was steadily expressed throughout the entire pregnancy while CaBP-9k was expressed strongly on PD12, and then declined sharply in PD15 before recovering slightly for the remainder of the pregnancy. Thus, the EGF family may play a key role during implantation in pigs. In addition, CaBP-9k may help maintain uterine quiescence during pregnancy by sequestering cytoplasmic Ca2+.

118. CHARACTERISATION OF HEPARAN SULPHATE PROTEOGLYCANS IN THE MATURING CUMULUS OOCYTE COMPLEX

2009 ◽  
Vol 21 (9) ◽  
pp. 37
Author(s):  
L. N. Watson ◽  
M. Sasseville ◽  
R. B. Gilchrist ◽  
D. L. Russell
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor ◽  
Heparan Sulphate ◽  
Cumulus Cells ◽  
Receptor Interaction ◽  
Heparan Sulphate Proteoglycans ◽  
Tgfβ Superfamily

Many growth factors including members of the transforming growth factor beta (TGFβ) superfamily and epidermal growth factor (Egf)-like ligands signal via interactions with heparan sulphate proteoglycans (HSPGs). Cell surface HSPGs can act by sequestering ligands at their site of action, by presenting a ligand to its signalling receptor, or by preventing ligand-receptor interaction. The oocyte secreted factors (OSF) growth differentiation factor 9 and bone morphogenetic protein 15 are members of the TGFβ superfamily that act selectively on cumulus cells. Conversely Egf-like ligands are secreted by mural granulosa cells and transmit LH-induced signals to cumulus cells. We investigated the possibility that HSPGs contribute to the spatially restricted responses these signals exert on cumulus cells. Syndecan-1 and Glypican-1 are cell surface HSPGs that are involved in numerous biological processes, including growth factor regulation, cell proliferation and differentiation. Microarray analysis showed Syndecan-1 and Glypican-1 mRNA expression induced 6-fold (P=10-9) and 3-fold (P=10-7) respectively in Egf+FSH stimulated cumulus oocyte complexes (COCs). Furthermore, Syndecan-1 and Glypican-1 mRNA were induced 27- and 16-fold respectively in COCs after hCG treatment of mice. Syndecan-1 and Glypican-1 protein was localised specifically to the COC through immunohistochemical analysis. In Vitro Maturation (IVM) of oocytes is a valuable alternative to gonadotropin mediated superovulation, but IVM COCs are less competent than those matured in vivo. Several components of the COC have been shown to be altered in IVM, including the chondroitin sulphate proteoglycan Versican. COCs from mice that underwent IVM in the presence of Egf+FSH and cilostamide for 16 hours had >16 fold reduced mRNA for Syndecan-1 when compared with In Vivo matured COCs. The lack of Syndecan-1 in IVM COCs could reduce signalling capacity of growth factors including OSFs. This may contribute to the reduced capacity of IVM oocytes to fertilise and produce a healthy embryo, and ultimately, a healthy offspring.

scholarly journals Contemporary concepts of uterine fibroids’ pathogenesis

2019 ◽  
Vol 10 (1) ◽  
pp. 91-99
Author(s):  
Anna N. Taits ◽  
Nikolai N. Ruhljada ◽  
Valeriy I. Matukhin ◽  
Aleksandra D. Somova ◽  
Kristina A. Dudova
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transforming Growth Factor ◽  
Uterine Fibroids ◽  
Transforming Growth Factor Β ◽  
Reproductive Age ◽  
Heparin Binding ◽  
Common Benign Tumor ◽  
Epidermal Growth

Uterine myoma is the most common benign tumor among women which affects mainly those of reproductive age. Moreover, the frequency of emergence of this pathology in population is growing while the age of patients is steadily decreasing. Despite the enormous prevalence of this disease, its pathogenesis has not been studied properly. This article is concerned with an analysis of publications devoted to the study of the mechanisms of growth and development of uterine fibroids, it provides some data on the role of various factors in its extension. The article concerns the most popular concepts of the pathogenesis of this disease according to which the illness may be caused by increased levels of sex hormones (estrogens and progestins), enhanced expression of their receptors, impaired apoptosis, the effect of growth factors (e. g. epidermal growth factor, heparin-binding epidermal growth factor, acid and basic fibroblast growth factors, vascular endothelial growth factor, insulin-like growth factor, platelet-derived growth factor, transforming growth factor-β, activin, myostatin), abnormal deposition extracellular matrix, genetic (chromosomal aberration and various MED12 gene defect) and epigenetic mechanisms (such as action microRNA), circulatory disorders and impairment of cell differentiation from a population of accessory stem cells. However, it is noted that the pathogenesis of this pathology requires further detailed study, as the understanding of the processes leading to its development could greatly contribute to the improvement of the tactics of treatment and possibly allow to elaborate some preventive measures to avert the development of fibroids.

Circulating keratan sulfate as a marker of metabolic changes of cartilage proteoglycan in juvenile idiopathic arthritis; influence of growth factors as well as proteolytic and prooxidative agents on aggrecan alterations

2015 ◽  
Vol 53 (2) ◽  
Author(s):  
Katarzyna Winsz-Szczotka ◽  
Katarzyna Komosińska-Vassev ◽  
Kornelia Kuźnik-Trocha ◽  
Andrzej Siwiec ◽  
Bogusław Żegleń ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Joint Damage ◽  
Keratan Sulfate ◽  
Control Group ◽  
Pretreatment Condition ◽  
Potential Marker ◽  
Tgf Β1

AbstractThe aim of this study was to evaluate the plasma keratan sulfate (KS) level as a potential marker of joint damage in children with juvenile idiopathic arthritis (JIA). The influence of growth factors as well as proteolytic and prooxidative agents on aggrecan alterations were evaluated in this study.Plasma levels of KS, transforming growth factor β1 (TGF-β1), platelet-derived growth factor BB (PDGF-BB), a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4 and ADAMTS-5), and thiol groups (TG) were quantified in samples obtained from 30 healthy subjects and 30 patients with JIA before and after treatment.Increased (p<0.01) plasma KS was observed in JIA patients before treatment. Therapy resulted in a decrease in KS level. However, plasma KS level remained higher (p<0.05) than in controls. Increased levels of TGF-β1 (p<0.01) and PDGF-BB (p<0.05) in untreated JIA patients were recorded. Clinical improvement was accompanied by significant decrease in TGF-β1 and PDGF-BB, compared with a pretreatment condition and a control group. The concentrations of proteinases were characterized by different trends of alterations. When the ADAMTS-4 level increased (p<0.01) in the blood of untreated patients, the concentration of ADAMTS-5 was found to be reduced (p<0.0001), compared with controls. JIA treatment resulted in the normalization of ADAMTS-4 level. Plasma TG concentration was decreased only in untreated patients (p<0.05). We have revealed a significant correlation between plasma KS level and ADAMTS-4, TGF-β1, TG, C-reactive protein, and erythrocyte sedimentation rate levels.Plasma KS level in JIA patients, reflecting the aggrecan structure, indicates that treatment that modifies inflammation simultaneously does not contribute to total regeneration of articular matrix components and signalizes the need for further treatment.

scholarly journals Transforming growth factor (type beta) promotes the addition of chondroitin sulfate chains to the cell surface proteoglycan (syndecan) of mouse mammary epithelia.

1989 ◽  
Vol 109 (5) ◽  
pp. 2509-2518 ◽  
Author(s):  
A Rapraeger
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Chondroitin Sulfate ◽  
Transforming Growth Factor ◽  
Core Protein ◽  
Protein Characterization ◽  
Tgf Beta ◽  
The Core ◽  
Cell Surface Proteoglycan

Cultured monolayers of NMuMG mouse mammary epithelial cells have augmented amounts of cell surface chondroitin sulfate glycosaminoglycan (GAG) when cultured in transforming growth factor-beta (TGF-beta), presumably because of increased synthesis on their cell surface proteoglycan (named syndecan), previously shown to contain chondroitin sulfate and heparan sulfate GAG. This increase occurs throughout the monolayer as shown using soluble thrombospondin as a binding probe. However, comparison of staining intensity of the GAG chains and syndecan core protein suggests variability among cells in the attachment of GAG chains to the core protein. Characterization of purified syndecan confirms the enhanced addition of chondroitin sulfate in TGF-beta: (a) radiosulfate incorporation into chondroitin sulfate is increased 6.2-fold in this proteoglycan fraction and heparan sulfate is increased 1.8-fold, despite no apparent increase in amount of core protein per cell, and (b) the size and density of the proteoglycan are increased, but reduced by removal of chondroitin sulfate. This is shown in part by treatment of the cells with 0.5 mM xyloside that blocks the chondroitin sulfate addition without affecting heparan sulfate. Higher xyloside concentrations block heparan sulfate as well and syndecan appears at the cell surface as core protein without GAG chains. The enhanced amount of GAG on syndecan is partly attributed to an increase in chain length. Whereas this accounts for the additional heparan sulfate synthesis, it is insufficient to explain the total increase in chondroitin sulfate; an approximately threefold increase in chondroitin sulfate chain addition occurs as well, confirmed by assessing chondroitin sulfate ABC lyase (ABCase)-generated chondroitin sulfate linkage stubs on the core protein. One of the effects of TGF-beta during embryonic tissue interactions is likely to be the enhanced synthesis of chondroitin sulfate chains on this cell surface proteoglycan.

scholarly journals Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors

2011 ◽  
Vol 210 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Mohan Singh ◽  
Parvesh Chaudhry ◽  
Eric Asselin
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Animal Studies ◽  
Transforming Growth Factor ◽  
Ethical Issues ◽  
Embryo Implantation ◽  
Transforming Growth Factor Β ◽  
Blastocyst Stage ◽  
Heparin Binding ◽  
Complex Molecules

The prerequisite of successful implantation depends on achieving the appropriate embryo development to the blastocyst stage and at the same time the development of an endometrium that is receptive to the embryo. Implantation is a very intricate process, which is controlled by a number of complex molecules like hormones, cytokines, and growth factors and their cross talk. A network of these molecules plays a crucial role in preparing receptive endometrium and blastocyst. Furthermore, timely regulation of the expression of embryonic and maternal endometrial growth factors and cytokines plays a major role in determining the fate of embryo. Most of the existing data comes from animal studies due to ethical issues. In this study, we comprehend the data from both animal models and humans for better understanding of implantation and positive outcomes of pregnancy. The purpose of this review is to describe the potential roles of embryonic and uterine factors in implantation process such as prostaglandins, cyclooxygenases, leukemia inhibitory factor, interleukin (IL) 6, IL11, transforming growth factor-β, IGF, activins, NODAL, epidermal growth factor (EGF), and heparin binding-EGF. Understanding the function of these players will help us to address the reasons of implantation failure and infertility.

scholarly journals Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate

1993 ◽  
Vol 122 (4) ◽  
pp. 933-940 ◽  
Author(s):  
S Higashiyama ◽  
JA Abraham ◽  
M Klagsbrun
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Cho Cells ◽  
Egf Receptor ◽  
Binding Domain ◽  
Heparin Binding ◽  
Heparin Binding Domain ◽  
Stimulation Of

Heparin-binding EGF-like growth factor (HB-EGF), but not EGF, binds to cell surface heparan sulfate proteoglycan (HSPG). This was demonstrated in (a) the binding of 125I-HB-EGF to mutant CHO cells deficient in HS production was diminished by 70% compared to wild-type CHO cells, (b) the binding of 125I-HB-EGF to CHO cells and bovine aortic smooth muscle cells (BASMC) was diminished 80% by heparitinase or chlorate treatment, and (c) 125I-EGF did not bind to CHO cells and its binding to BASMC was not diminished at all by heparitinase and only slightly by chlorate treatment. Accordingly, the role of HB-EGF interactions with HSPG in modulating bioactivity was examined. Heparitinase or chlorate treatment of BASMC diminished the ability of HB-EGF to stimulate BASMC migration by 60-80%. A similar inhibition of migration occurred when BASMC were treated with a synthetic peptide (P21) corresponding to the sequence of the putative heparin-binding domain of HB-EGF. As a control for BASMC viability, and for specificity, it was found that heparitinase and P21 did not inhibit at all and chlorate inhibited only slightly the stimulation of BASMC migration by PDGF AB. Since heparitinase, chlorate, and P21 treatment also diminished by 70-80% the cross-linking of 125I-HB-EGF to the EGF receptor, it was concluded that the interaction of HB-EGF, via its heparin-binding domain, with cell surface HSPG was essential for its optimal binding to the EGF receptor on BASMC and hence for its optimal ability to stimulate migration.

scholarly journals Heparan Sulfate Acts as a Bone Morphogenetic Protein Coreceptor by Facilitating Ligand-induced Receptor Hetero-oligomerization

2010 ◽  
Vol 21 (22) ◽  
pp. 4028-4041 ◽  
Author(s):  
Wan-Jong Kuo ◽  
Michelle A. Digman ◽  
Arthur D. Lander
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Bone Morphogenetic Proteins ◽  
Growth Factor Receptor ◽  
In Vivo Studies ◽  
Type I ◽  
Receptor Complexes

Cell surface heparan sulfate (HS) not only binds several major classes of growth factors but also sometimes potentiates their activities—an effect usually termed “coreception.” A view that coreception is due to the stabilization of growth factor–receptor interactions has emerged primarily from studies of the fibroblast growth factors (FGFs). Recent in vivo studies have strongly suggested that HS also plays an important role in regulating signaling by the bone morphogenetic proteins (BMPs). Here, we provide evidence that the mechanism of coreception for BMPs is markedly different from that established for FGFs. First, we demonstrate a direct, stimulatory role for cell surface HS in the immediate signaling activities of BMP2 and BMP4, and we provide evidence that HS–BMP interactions are required for this effect. Next, using several independent assays of ligand binding and receptor assembly, including coimmunoprecipitation, cross-linking, and fluorescence fluctuation microscopy, we show that HS does not affect BMP binding to type I receptor subunits but instead enhances the subsequent recruitment of type II receptor subunits to BMP-type I receptor complexes. This suggests a view of HS as a catalyst of the formation of signaling complexes, rather than as a stabilizer of growth factor binding.

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