fibroblast growth factor receptor 2

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Identifizierung von Genen, die durch fibroblast growth factor receptor 2 (FGFR2) reguliert werden

Identifizierung von Genen, die durch fibroblast growth factor receptor 2 (FGFR2) reguliert werden

Bei den Untersuchungen zur Fyn-Expression waren ebenfalls in einem der drei oben beschriebenen Experimente keine Expressionsdifferenzen innerhalb einer Inkubationsdauer mit und ohne FGF2 zu beobachten. In den beiden anderen Versuchen waren zwar Fyn-Expressionsunterschiede innerhalb einer Inkubations- dauer mit und ohne FGF2 detektierbar. Jedoch waren diese Differenzen hinsichtlich Qualität und Zeitfenster der FGF2-Inkubation verschieden von dem Fyn- Expressionsmuster, das in Abbildung 3.19 dargestellt ist (Abbildung 3.21). Zum einen war die Expression der 3,8 kB langen Fyn-mRNA schon nach wesentlich kürzeren FGF2-Inkubationszeiten vermindert. Sie erfolgte in den beiden in Abbildung 3.21 dargestellten Versuchen nach 1 und 2 Stunden FGF2-Inkubation der WT26-Zellen, bei dem in Abbildung 3.19 dargestellten Versuch hingegen nach 6 Stunden FGF2- Inkubation. Die Stärke der Repression der 3,8 kB-mRNA lag dabei in den beiden in Abbildung 3.21 dargestellten Versuchen bei 1,7 und war damit etwas schwächer als bei dem in Abb. 3.19 dargestellten initialen Versuch (dort 2,2 -fach). Zum anderen kam es in keinem der drei Reproduktionsversuche zu einer Zunahme der Expression der 2,8 kB langen Fyn-mRNA nach FGF2-Inkubation. Stattdessen wurde in 2 Experimenten im jeweils gleichen Zeitfenster wie für die lange Fyn-mRNA eine Abschwächung der Expression detektiert (1,4-fach nach 2 Stunden und 1,3-fach nach 3 Stunden bzw. 1,8 -fach nach 1 Stunde und 1,2 -fach nach 2 Stunden).
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Evaluation of the Fibroblast Growth Factor Receptor 2 (FGFR2) in Experimental Autoimmune Encephalomyelitis (EAE) and its Possible Role in Multiple Sclerosis (MS)

Evaluation of the Fibroblast Growth Factor Receptor 2 (FGFR2) in Experimental Autoimmune Encephalomyelitis (EAE) and its Possible Role in Multiple Sclerosis (MS)

The fibroblast growth factor (FGF) family is a group of multifunctional signalling molecules which are involved in numerous cellular processes such as proliferation, migration, and differentiation and various physiological processes such as mitogenesis, angiogenesis, embryogenesis, regulating metabolism and wound healing (Teven et al., 2014). FGF growth factors have been identified in various multicellular organisms from the nematode to humans (Itoh, 2007). In mammals, the FGF family consist of 22 structurally related proteins (Woodbury and Ikezu, 2013). Based on the modes of action, mechanisms of secretion and ultimate biological consequences, these proteins have been further grouped into several subfamilies, each sharing both genetic and functional similarity. They include FGF1 subfamily (FGF1 and FGF2), FGF4 subfamily (FGF4, FGF5, FGF6), FGF7 subfamily (FGF3, FGF7, FGF10 and FGF22), FGF8 subfamily (FGF8, FGF17 and FGF18), FGF9 subfamily (FGF9, FGF16 and FGF20), FGF19 subfamily (FGF19, FGF21 and FGF23), and FGF homologous factor (FHF) subfamily (FGF11 (FHF3), FGF12 (FHF1), FGF13 (FHF2), and FGF14 (FHF4)) (Imamura, 2014). FGFs share a similar internal core and have a characteristically high binding affinity for both heparin and fibroblast growth factor receptors (FGFRs) (Teven et al., 2014). They exert their activities mainly via paracrine and/or autocrine modes of action by activating one or more cell surface receptor tyrosine kinases (Imamura, 2014).
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Analyses of fibroblast growth factor signaling in lung fibrosis

Analyses of fibroblast growth factor signaling in lung fibrosis

FGF7, otherwise known as keratinocyte growth factor (KGF), binds with high affinity and exclusively to FGFR2-IIIb (Cheon et al., 1994; Mason et al., 1994). While FGF7 shows potent mitogenic activity on epithelial cells, as FGFR2- IIIb is expressed exclusively on epithelial cells, no corresponding activity on fibroblasts, endothelial cells, melanocytes, or other non-epithelial targets of FGF action have been observed (Aaronson et al., 1991). In addition to high receptor specificity, a precise conformation of HSPGs with specific charge densities between stromal and epithelial cells in the ECM, are also necessary in order for FGFR2-IIIb to access stromal-derived FGF7 (Luo et al., 2006a; Luo et al., 2006b). In vitro studies showed that FGF7 induced activation of FGFR2-IIIb, elicited tyrosine phosphorylation not only of FRS2 α , but also of the insulin receptor substrate 4 (IRS4), the canonical extracellular signal regulated kinase 2 (ERK2, MAPK2), and cyclin-dependent protein kinase (CDK2) (Luo et al., 2009). In the lung, FGF7 plays an important role in mediating the proliferation, migration and differentiation of AEC2 cells (Deterding et al., 1996). Treatment of isolated adult lung type II cells (AEC2) with FGF7 increases expression of the surfactant-associated proteins SP-A and SP-B, with no effect on SP-C mRNA expression (Sugahara et al., 1995). In addition it has been shown to regulate fluid balance in the fetal lung (Zhou et al., 1996) possibly via up-regulation of aquaporin-5 (AQP5) expression, an epithelial water channel (Tichelaar, 2000). Interestingly, FGF7 also stimulates lipogenesis in rat AEC2 cells by inducing expression of lipogenic enzymes and transport proteins regulated by transcription factors CCAAT/enhancer-binding protein (C/EBP) isoforms and sterol regulatory element-binding proteins (SREBP), but not peroxisome proliferation activator receptor gamma (PPAR γ ). Notably, FGF7 induces fatty acid synthase, stearoyl- CoA desaturase-1 (SCD-1), which activates fatty acid synthesis in AEC2 cells (Mason et al., 2003).
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Molecular networks in FGF signaling : Flotillin-1 and Cbl-associated protein compete for the binding to fibroblast growth factor receptor substrate 2

Molecular networks in FGF signaling : Flotillin-1 and Cbl-associated protein compete for the binding to fibroblast growth factor receptor substrate 2

Fibroblast growth factor receptor substrate 2 (FRS2a) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases. During signal transduction, FRS2 can be both tyrosine and threonine phosphorylated and forms signaling complexes with other adaptor proteins and tyrosine phosphatases. We have here identified flotillin-1 and the cbl-associated protein/ponsin (CAP) as novel interaction partners of FRS2. Flotillin-1 binds to the phosphotyrosine binding domain (PTB) of FRS2 and competes for the binding with the fibroblast growth factor receptor. Flotillin-1 knockdown results in increased Tyr phosphorylation of FRS2, in line with the inhibition of ERK activity in the absence of flotillin-1. CAP directly interacts with FRS2 by means of its sorbin homology (SoHo) domain, which has previously been shown to interact with flotillin-1. In addition, the third SH3 domain in CAP binds to FRS2. Due to the overlapping binding domains, CAP and flotillin-1 appear to compete for the binding to FRS2. Thus, our results reveal a novel signaling network containing FRS2, CAP and flotillin-1, whose successive interactions are most likely required to regulate receptor tyrosine kinase signaling, especially the mitogen activated protein kinase pathway.
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Fibroblast Growth Factor Receptor 1 trafficking in human glioma cells / Dr.in med. univ. Regina Brigitta Irschick

Fibroblast Growth Factor Receptor 1 trafficking in human glioma cells / Dr.in med. univ. Regina Brigitta Irschick

Statistical analysis and representation of graphs was performed with Microsoft Excel and GraphPad Prism 5 software. For all statistical analyses, data from at least three independent experiments were pooled. Usually the data were normalized to the control group of each experiment, which was set at 100%. Statistical analysis was performed using Student´s t-test (unpaired) to compare two independent groups, or one-way analysis of variance (ANOVA) when more than two groups were compared. The ANOVA was followed by Tukey’s post hoc test or Bonferroni analysis when the datasets were too large for Tukey´s post test. The differences between the groups were considered as statistically significant if the p-value was < 0.05, and are presented in the graphs with one, two or three stars according to their levels of significance (* p < 0.05, ** p < 0.01 or *** p < 0.001 = output of Graph Pad Prism 5). If not indicated otherwise, the levels of significance shown in the graphs were obtained from the comparison of the treated groups with the untreated control group, which is shown as a black column in the graphs. All data points are presented as mean values ± standard error of the mean (SEM) or standard deviation (SD) applying GraphPad Prism 5 software. The number of analyzed values (i.e. the amount of analyzed cells, lysates, FACS samples or the number of obtained object values) is indicated inside each bar. The x-fold changes of the different mRNA levels were calculated from the Ct-values according to the ΔΔCt-method (1/((sham1- exp1) 2 /(sham2-exp2) 2 ). For the object density of FGFR1, Lamp1 and transferrin, the area under the curve (AUC) was calculated by integrating the fitted curve of the objects´ density at various levels within the three-dimensional cells and plotting it with Matlab (as shown in Figure 3.29 or Supplementary Figure 1 in Irschick et al. 2013).
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Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis

Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis

in SW620 cells that showed the lowest FGFR3-IIIc expression in our cell line panel. As PD173074 targets other FGFRs as well as FGFR3, we cannot exclude that these FGFRs also counteract IRI response. However, two observations argue against this possibility: 1) other FGFRs are not upregulated by exposure to the drug, and 2) FGF18, which is high in most colon cancer cells, and FGF8, which is induced by IRI, are mainly FGFR3 ligands [11] . Increased mRNA levels for FGFR3-IIIc as well as its ligands FGF8 and FGF18 were also found in xenograft tumors treated with IRI, indicating that the survival response also takes place in vivo. It may be the reason that IRI alone was not very effective against HCT116-xenograft tumors. Tumors in the IRI treatment group grew more slowly, but subsequent administration of PD173074 reduced tumor growth to almost zero. Consequently, tumors were too small to analyze efficiency of apoptosis in the tissue.
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Structural characterization of the interaction of the fibroblast growth factor receptor with a small molecule allosteric inhibitor

Structural characterization of the interaction of the fibroblast growth factor receptor with a small molecule allosteric inhibitor

either no effect or a decrease in melting temperature (S14). The increased protein stability of the H349A mutant, together with its higher K D value for SSR binding, supports H349 to be a key amino acid in the FGFR3cD3 interaction with SSR (S14). Isothermal titration calorimetry (ITC) confirmed the NMR de- termined affinities of FGFR3cD3 wild-type and its mutants to the SSR inhibitor despite a high noise level (S16 and S17). The FGFR3cD3 wild-type and its H327D mutant revealed a mm- binding (Figure 2 B). In contrast, the H349D FGFR3cD3 mutant and its H327DH349D double mutant do not show binding to SSR. Due to the low solubility of SSR in aqueous buffers, we used a titration scheme with lower injection numbers but higher volume of single injections to observe the small molar enthalpy of the interaction. The FGFR3cD3-SSR titration profile shows a very low binding enthalpy, almost at the edge of de- tection and yields a K D in the 50–100 mm range, confirming the
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Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer - a putative therapeutic target for a small subgroup

Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer - a putative therapeutic target for a small subgroup

FGFR3-rearrangement analysis (break apart FISH and cDNA fragment analysis) FISH analysis for FGFR3 rearrangement was effectively performed on a total of 66 samples. For each tissue microarray we evaluated cores of normal urothelium, showing a mean of 4.22 break apart events. According to Wolff et al. we calculated a cut off for positive cases by using the Microsoft Excel β-inverse function BETAINV [14]. Tumor samples were scored as positive, if nine or more break apart events in 60 tumor cell nuclei were found (Figure 1, Supplementary Data S1). We identified only eight slightly positive samples (ranging from 9 to 11 break apart events, mean 9.5 events/sample). There was no overlap with the polysomic samples mentioned above. Additional cDNA fragment analysis of FISH-positive cases showed sufficient FGFR3-cDNA in two available frozen samples (ID #2, #18), but no FGFR3-TACC3-fusion product could be verified.
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Characterization of the role of fibroblast growth factor 10 (Fgf10) and its receptor Fgfr2b on multipotent epithelial progenitor cells during early lung development

Characterization of the role of fibroblast growth factor 10 (Fgf10) and its receptor Fgfr2b on multipotent epithelial progenitor cells during early lung development

About 50 cell types were recognized in the adult mouse lung, these cells can be classified into epithelial and mesenchymal cells. Epithelial cells populate the airways and start to emerge during the pseudoglandular stage: basal, ciliated, neuroendocrine and secretory cells; whereas the mesenchymal cells populate the surrounding extracellular matrix: airway smooth muscle cells (ASMCs), vascular smooth muscle cells (VSMCs), endothelial cells, nerve cells, cartilage and lymphatics. The type I and type II alveolar epithelial cells (AECI, AECII) start to appear during the canalicular stage (E16.5). The proximal region of the mouse lung includes the trachea, which is a ringed-cartilaginous tube, and the main bronchi (which also display cartilage in their most proximal part). This region is populated by basal, goblet, ciliated, clara and neuroendocrine cells. The distal region lack cartilage and mucin producing cells and comprises bronchioles which end into alveolar sacs; it contains few goblet, ciliated, secretory, and alveolar epithelial cells which differentiate between E16.5 and E18.5 into AECI and AECII. AECI are squamous epithelial cells that occupy 95% of alveolar space and responsible for gas exchange. AECII are cuboidal epithelial cells responsible for surfactant production that prevent the alveoli from collapsing (Rawlins and Hogan, 2006; Rock et al., 2010; Rock and Hogan, 2011; McQualter and Bertoncello, 2012) (Figure 2). It has been proposed that AECI and AECII lineages emerge from a common alveolar bipotential progenitor (BP) cells (Treutlein et al. 2014; Desai et al., 2014).
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Studies on the regulation of the phosphaturic hormone fibroblast growth factor 23 (FGF23)

Studies on the regulation of the phosphaturic hormone fibroblast growth factor 23 (FGF23)

The fibroblast growth factor (FGF) superfamily affects an extremely broad range of biological processes such as development, organogenesis, and metabolism. This is feasible due to the large number of 22 members (FGF1-FGF23). FGF15 is the murine orthologue to human FGF19 and is therefore often summarized as FGF15/19 [1]. Most FGFs mediate their effect by binding to cell surface FGF receptors (FGFR). Four genes (FGFR1-4) encode for these receptor tyrosine kinases. Two isoforms (b and c) exist by alternative splicing of FGFR1-3 [2]. The 22 human members are divided into 7 subfamilies based on their phylogenetic origin and sequence homology [3]. FGFs of the FGF1, FGF4, FGF7, FGF8 and FGF9 subfamily act as paracrine/autocrine factors. A special feature of the FGF11 subfamily, also called FGF homologous factors, is that they do not bind to FGFRs and act as intracellular mediators [4], for example, by binding to intracellular domains of voltage-gated sodium channels and thus modulate subcellular transport [5]. The FGF19 subfamily, which hosts FGF19/15, 21, and 23, functions as circulating factors and is referred to as endocrine FGFs [3].
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Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo

Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo

Local application of chondrocytes secreting human FGF-2 via spheres to cartilaginous defects may avoid a potential dilution of the factor in the synovial fluid and/or its uptake by synovial cells. It may thus prevent the development of an inflammation of the knee joint. Indeed, by 3 weeks in vivo there was a sustained production of FGF-2 by spheres that may have lasted for more than 4 weeks as previously determined using a reporter gene [21]. The absence of elevated FGF-2 levels in the synovial fluid at 3 weeks is probably due to the containment of the transgene product within the spheres and the new tissue in the defect. This supports the hypothesis of local growth factor production and action and suggests that this method of ex vivo gene delivery does not elicit any undesirable immune response. The decline of FGF-2 transgene expression in vitro has been recently demonstrated using a recombinant adeno-associated viral (rAAV) vector in a similar system [44]. FGF-2 is a secreted factor that remains mostly attached to its receptor at the surface of the genetically modified cells. The levels of FGF-2 might thus be underestimated by the ELISA. A lack of elevated intraarticular FGF-2 and of inflammatory changes of the synovial membrane may be advantageous in a clinical setting, in order to avoid undesired effects of the therapeutic factor such as observed in synovial hyperplasia [36,37].
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Korrelation von placental growth factor, vascular endothelial growth factor und soluble vascular endothelial growth factor receptor-1 im Serum mit Tumorstadien und Prognose des hepatozellulären Karzinoms

Korrelation von placental growth factor, vascular endothelial growth factor und soluble vascular endothelial growth factor receptor-1 im Serum mit Tumorstadien und Prognose des hepatozellulären Karzinoms

Im fortgeschrittenen Tumorstadium BCLC C liegt die 1-Jahres-Überlebensrate bei 25% (Tu- mor mit makroskopischer Gefäßinvasion oder extrahepatischer Manifestation sowie bei Thera- pieversagen lokoregionaler Verfahren). Bei Patienten mit einer erhalten Leberfunktion kommt seit 2007 der Tyrosinkinasehemmer Sorafenib zum Einsatz. Allerdings ist der Überlebensvor- teil gering und bereits bei Child-Pugh-Stadium B minimal (32). Neben den modifizierten RE- CIST-Kriterien ist vor allem das klinische Ansprechen und die Toleranz für das Therapiema- nagement ausschlaggebend (8). Der Wirkmechanismus führt über Hemmung der B-Raf- und Raf-1-Kinase sowie der Tyrosinkinasen des vascular endothelial growth factor recep- tor (VEGFR) und des platelet-derived growth factor receptor (PDGFR) zu einer Hemmung der Angiogenese (Kapitel 5.1.3), der Zellproliferation und zu einer Reduktion der Tumorlast (33). Die wichtigsten Nebenwirkungen sind das Hand-Fuß-Syndrom, gastrointestinale Beschwerden und arterieller Hypertonus. Bis zu 30% der Patienten müssen aufgrund der schlechten Toleranz die Therapie abbrechen (34). Lenvatinib inhibiert VEGF- R1-3, fibroblast growth factor recep- tor 1-4 (FGF-R1-4), platelet-derived growth factor receptor alpha (PDGFR-α) und die Wachs- tumsfaktor-Rezeptoren RET und KIT und wird neuerdings ebenfalls als Erstlinientherpie enge- setzt. Seit Kurzem gibt es mit Regorafenib, einem oralen Multikinaseinhibitor mit ähnlichem Wirkmechanismus, eine Zweitlinientherapie bei Therapieversagen unter Sorafenib. Cabozanti- nib hemmt die Tyrosinkinasen MET, RET und VEGF-R2 und wurde ebenfalls als Zweitlinien- therapie bei erfolgloser oder nicht vertragener Therapie mit Sorafenib zugelassen (1). Neuer- dings wurde zudem Ramucirumab, ein monoklonaler Antikörper gegen VEGFR-2, als Zweit- linientherapie bei erhöhtem AFP zugelassen (35).
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Tumorvakzinierung gegen den "Vascular Endothelial Growth Factor Receptor 2" (VEGFR2)mittels heterologem Antigentransport durch rekombinante Salmonellen

Tumorvakzinierung gegen den "Vascular Endothelial Growth Factor Receptor 2" (VEGFR2)mittels heterologem Antigentransport durch rekombinante Salmonellen

eine Endothelzelle mehrere Hundert Tumorzellen versorgt (109). Ein weiterer Vorteil ist, dass die proliferierenden Endothelzellen im Tumorgefäßsystem gut zugänglich für die CTLs sind. In bisherigen klinischen Studien wurden hauptsächlich Antikörper zur Anti-Angiogenese Immuntherapie verwendet. In zahlreichen präklinischen und klinischen Entwicklungsstudien wurden auch andere Ansätze getestet, um eine Immuntherapie gegen Krebs mittels Anti- Angiogenese durchzuführen. Dabei wurden unter Anderem fixierte Endothelzellen (147), VEGFR2-konjugierte Proteine (148), VEGFR2-gepulste DCs (109;110), liposomale Peptide des „fibroblast growth factor-2“ (149) und verschiedene DNA-Vakzine gegen Survivin, Integrin β 3 , VEGF und VEGFR2 (150) zur anti-angiogenen Immunisierung verwendet. Neuere Studien im Mausmodell haben gezeigt, dass die Tumorangiogenese mit Hilfe einer DNA-Vakzinierung durch die Induktion einer zellulären Immunantwort gegen den „Vascular endothelial growth factor receptor 2“ (VEGFR2) blockiert werden kann (96). Dieser DNA- Impfstoff schützte Mäuse effektiv vor dem Wachstum von Melanom-, Kolonkarzinom- und Lungenkarzinomzellen und reduzierte das Auftreten von Metastasen in einem präventiven Versuchsansatz. Außerdem wurden auch virale Vektoren zur DNA-Vakzinierung gegen VEGFR2 im Mausmodell eingesetzt, um das Wachstum und die Metastasierung von Lungenkarzinomen und Melanomen zu inhibieren (151).
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Mutationen in den "fibroblast growth factor" (FGF) -Rezeptorgenen FGFR 1, 2 und 3 bei primären Craniosynostosen

Mutationen in den "fibroblast growth factor" (FGF) -Rezeptorgenen FGFR 1, 2 und 3 bei primären Craniosynostosen

Die FGF-Rezeptoren beginnen extrazellulär mit einem N-terminalen Signalpeptid. Der extrazelluläre Bereich beinhaltet weiterhin eine charakteristische Abfolge der Aminosäure Cystein. Diese Cysteine sind über Disulfidbrücken stabilisiert, was die Gestalt der 3 aufeinanderfolgenden sogenannten Immunglobulin-ähnlichen Domänen (Ig I-III) ausmacht. Jede der Ig-Domänen wird nämlich durch eine solche Disulfidbrücke stabilisiert. Zwischen Ig I und Ig II befindet sich die sogenannte „acid box“, eine Häufung der sauren Aminosäuren Asparaginsäure und Glutaminsäure, darüberhinaus liegen dort die drei Aminosäuren: Histidin, Alanin und Valin (HAV). Diese sogenannte HAV-Struktur wurde schon in den Zelladhäsionsmolekülen N-cam, L-cam und N-cadherin gefunden. Es wird vermutet, dass HAV eine Rolle bei der Bindung zwischen Molekülen spielt (Burke et al., 1998; Plotnikov et al., 1999). Den 3 Ig-Domänen folgt die aus hydrophoben Aminosäuren bestehende transmembrane Domäne (TM). Es schließt sich der zytoplasmatische Bereich an, bestehend aus der juxtamembranen Domäne, sowie der durch 14 Aminosäuren gespaltenen Tyrosinkinase Domäne (TK 1 und TK 2). Den abschließenden Teil stellt die carboxyterminale Region dar. Durch alternatives „splicing“ der m-RNA entstehen zusätzliche Formen der Rezeptoren. Dabei werden verschiedenste Rezeptorformen gebildet. So kann zum Beispiel die Ig I-Domäne mit oder ohne „acid box“ herausgeschnitten werden. Von der zweiten Hälfte der Ig III-Domäne sind 2 Isoformen bekannt, für die 2 verschiedene Exons kodieren. In FGFR 2 kodiert Ig IIIb für den Keratinocytenwachstumsfaktor („Keratinocyte Growth Factor Receptor = KGFR“) und bindet als Liganden FGF 1 und KGF („KGF = Keratinocyte Growth Factor“). Ig IIIc („bek = bacterial expressed kinase“) definiert den FGF-Rezeptor 2 und bindet FGF 1 und 2 mit gleich hoher Affinität, jedoch nicht KGF (Keratinocyte Growth Factor = FGF 7). Essenziell für die Bindung eines Liganden sind die Ig-Domänen II und III, während Ig I für die Bindung nicht erforderlich ist (Plotnikov et al., 1999).
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The Fibroblast Growth Factor-binding Protein (FGF-BP) and the Human Epidermal Growth Factor Receptor-2 (HER-2): functional studies on two gene products relevant in Ovarian cancer

The Fibroblast Growth Factor-binding Protein (FGF-BP) and the Human Epidermal Growth Factor Receptor-2 (HER-2): functional studies on two gene products relevant in Ovarian cancer

Anchorage-independent growth assay correlates strongly with tumorigenicity and invasiveness in several cell types, e.g. small-cell lung carcinoma [353]. For this reason soft agar assays were performed using SW-13 and COS-7 cells stably transfected with various FGF-BP constructs to analyze the biological significance of the interaction of full length and various truncated FGF-BP mutants with FGF-2. As expected, stimulating effects of full length FGF-BP on the colony formation of SW-13 cells were observed. The similar effects have been demonstrated in previous studies [88,93]. Furthermore, through the blocking of colony formation of FGF-BP-transfected SW-13 cells by a specific antibody against FGF-2 it was demonstrated that the tumorgenic potential of FGF-BP is FGF-2-dependent [88]. These previous studies provide indirect evidence that FGF-BP can stimulate tumor growth by releasing and activating endogenous FGF-2 from the extracellular matrix (ECM). Based on the confocal microscopy data regarding the nuclear localization of FGF-BP in SW-13 cells, an intracellular mechanism of the stimulating function of FGF-BP based on its interaction with nuclear FGF-2 cannot be excluded. This suggestion is supported by the loss of FGF-BP- mediated colony formation of SW-13 cells upon stable transfection with N-terminal truncated FGF-BP constructs (BP-C-91 and BP-C-146), which in confocal microscopy did not show nuclear colocalization and interaction with FGF-2.
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Fibroblast growth factor receptor 3 and irinotecan resistance in colorectal cancer / submitted by Zeynep Nesli Erdem

Fibroblast growth factor receptor 3 and irinotecan resistance in colorectal cancer / submitted by Zeynep Nesli Erdem

Cancer cells can create a growth advantage by increasing oncogene expression (e.g. ras) and self-production of growth signals. Many types of cancers produce autocrine ligands like fibro- blast growth factor 2 (FGF2) and transforming growth factor α (TGFα). Increased expression of growth factor receptors leads to overshooting responses even in the absence of ligands (Figure 1.1). This phenomenon happens in cases such as the amplification of a growth factor receptor. Prominent examples come from the epidermal growth factor receptor (EGFR) family: many copies of Her2 gene can be found in 1 of 4 breast cancer patients [4]. Also EGFR is am- plified in glioma, an aggressive form of brain tumour [5, 6]. Chromosomal translocations may also lead to generation of oncogenes as was described for the Philadelphia chromosome. There, BCR-ABL fusion protein leads to the constitutive activation of ABL oncogene leading to acute lymphoid (ALL) [7] and chronic myeloid leukaemia (CML) [8]. Also chromosome 2 inversions that lead to EML4-ALK fusion protein in non-small cell lung carcinoma (NSCLC) [9] and in- creased FGFR3 expression in multiple myeloma through t(4;14) [10, 11] have been shown. An- other mechanism of oncogene activation is through activating mutations in the kinase domain leading to a constitutive firing of signals intracellularly. This has been shown for EGFR L858R
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Evaluation of the fibroblast growth factor receptor 1 (FGFR1) in experimental autoimmune encephalomyelitis (EAE)

Evaluation of the fibroblast growth factor receptor 1 (FGFR1) in experimental autoimmune encephalomyelitis (EAE)

FGF receptor signalling mediating major cancer types in human beings. FGFR1 amplification is involved in breast, lung, squamous cell carcinoma, esophageal, ovarian and osteosarcoma (Dienstmann et al. 2014). Table 2 shows the involvement of FGFR1 in various cancer types in human beings. FGF signalling involved in many metabolic processes such as phosphate and vitamin D homeostasis, cholesterol and bile acid homeostasis, and glucose/lipid metabolism (Belov and Mohammadi 2013). Endocrine FGFs also involved in metabolic disorders such as chronic kidney disease, obesity and insulin resistance (Belov and Mohammadi 2013). Whereas, FGF/FGFR pathway implicated in the protection of neurons against neurotoxins and FGF have been shown to protect neurons by down-regulating the expression of the chemokine receptor CXCR4, activating cell-survival signalling and inhibiting the internalization of HIV-1 coded proteins (Sanders et al. 2000, Bachis et al. 2003). At least three genetic disorders can be attributed to mutations in FGFR1: Kallman´s syndrome, ostroglophonic dysplasia and Pfeiffer´s syndrome. Pathological Fgfr1 signalling also occurs in various malignancies (Beenken and Mohammadi 2009) (Table 2).
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Regulation des glialen Glutamattransports durch den Wachstumsfaktor ''Fibroblast growth factor 2'' (FGF-2)

Regulation des glialen Glutamattransports durch den Wachstumsfaktor ''Fibroblast growth factor 2'' (FGF-2)

Aus den zerebralen Hemisphären wurden primäre Gliakulturen angelegt, indem zunächst unter sterilen Bedingungen der Schädel eröffnet wurde, die Hemisphären herauspräpariert und die Meningen sorgfältig entfernt wurden. Die Gewebstücke wurden in eisgekühltem N2-Medium gesammelt, anschließend mit der Schere zerkleinert und dann für 20 min bei Raumtemperatur in 0,1%iger Trypsinlösung inkubiert. Die Trypsinwirkung wurde durch Überführen der Gewebsstücke in Hanks-gepufferte-Salzlösung mit 10% fetalem Kälberserum gestoppt. Die anverdauten Gewebsstücke wurden durch mehrmaliges Auf- und Abpipettieren in 10 ml Kunststoff-Pipetten dissoziiert. Nicht zerkleinerte Stückchen wurden mittels Filtrieren durch ein Nitex-Netz mit 20 µm Porengröße entfernt. Die erhaltene Zellsuspension wurde 5 min bei 400 g zentrifugiert und das Zellpellet in vollständigem Kulturmedium (MEM mit 10% Pferdeserum) resuspendiert. Diese Zellsuspension wurde nun auf 100-mm-Zellkulturschalen verteilt, so dass die pro Schale ausgesäte Zellmenge etwa drei präparierten Rattenhirnen entsprach. Durch Zugabe von vollständigem Kulturmedium wurde ein Gesamtvolumen von 10 ml/Schale erhalten. Die Kulturschalen waren zuvor für 1 h mit 0,1 mg Poly-D-Ornithin/ml gecoatet und danach mit sterilem Wasser gespült worden. Die Zellkulturen wurden bei 37°C in einer Atmosphäre aus 90% Luft und 5% CO 2 bei 100% Luftfeuchtigkeit inkubiert. Das Medium wurde zum
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Targeting insulin-like growth factor - I receptor in breast cancer

Targeting insulin-like growth factor - I receptor in breast cancer

Evidence suggests crosstalk between IGF-IR and ErbB2 in breast cancer cells in vitro, but little data exists on the interplay between these growth factor receptors in initiating mammary tumorigenesis in vivo. Therefore, we assessed the ability of a dominant active IGF- IR (CD8-IGF-IR) to promote mammary tumorigenesis of mice that overexpress ErbB2. We identified that mice expressing both oncogenes (CD8-IGF-IR and ErbB2) developed tumors significantly faster compared to either transgene alone. Interestingly, tumors overexpressing CD8-IGF-IR displayed expansion of K14 positive myoepithelial cells and progenitor cells expressing K6. Analysis of co-operativity between ErbB2 and IGF-I was complicated by the data suggesting that IGF-IR and ErbB2 transform different progenitor cell types. To investigate this, I developed a mouse modeling system using avian RCAS retrovirus as a vehicle to deliver CD8-IGF-IR or ErbB2 into transgenic mice expressing the avian receptor TVA under the control of a MMTV promoter. This allows retroviral infection of specific mammary cell types in vivo. Mammary intraductal injection of RCAS-CD8-IGF-IR into mice has shown expression of CD8-IGF-IR. After six weeks, CD8-IGF-IR caused hyperplastic lesions in MMTV-TVA mice with expansion of myoepithelial cells expressing K14. However, up to date we have not detected tumors arising from CD8-IGF-IR overexpression.
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Knochenmikroarchitektur, Fibroblast Growth Factor-23 und Sclerostin bei Patienten mit osteoporotischer Fraktur : ein Vergleich zwischen pertrochantärer und Schenkelhalsfraktur

Knochenmikroarchitektur, Fibroblast Growth Factor-23 und Sclerostin bei Patienten mit osteoporotischer Fraktur : ein Vergleich zwischen pertrochantärer und Schenkelhalsfraktur

FGF-23 ist ein 32 kDa schweres und 251 Aminosäuren langes Protein, das vornehmlich in Osteozyten und Osteoblasten gebildet wird. Es gehört mit FGF-19 und FGF-21 zur Unterfamilie der endokrin wirksamen FGF. Ihnen allen ist eine Affinität zu einem der 4 Fibroblast Growth Factor Rezeptoren (FGFR, Typ 1 Transmembranphoshotyrosinkinase) gemein. FGF-Proteine benötigen in der Regel Heparansulfatglycosaminoglykane zur Signaltransduktion und sind u.a. an Embryoge- nese, Angiogenese, Wundheilung und Tumorwachstum beteiligt (Powers, McLeskey et al. 2000; Kovesdy 2014). Die heparinbindende Domäne des FGF-23 unterscheidet sich strukturell von denen der typischen Vertreter der FGF-Familie, sodass seine Affinität für die FGFR herabgesetzt wird. Als Cofaktor benötigt es das Protein alpha-Klotho (Martin, David et al. 2012).
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