Fibroblast growth factors, their receptors and signaling.
TL;DR: FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.
Abstract: Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where theycan bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs mayact directlyon target cells, or theycan be released through digestion of the ECM or the activityof a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimatelyresulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most playimportant roles in embry onic development and wound healing. FGF signaling also appears to playa role in tumor growth and angiogenesis, and autocrine FGF signaling maybe particularlyimportant in the progression of steroid hormone-dependent cancers to a hormone-independent state.
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Patent•
22 Dec 2005Abstract: The present invention pertains to certain 6-carboaryloxy-pyrazin-2-yl-carboaryl-amines of the following formula, and pharmaceutically acceptable salts thereof, which, inter alia, inhibit RAF (e.g., B-RAF) activity, inhibit cell proliferation, treat cancer, etc., wherein Q is independently —N═; R P3 is independently a group of the formula -J 1 -L 1 -Z; -J 1 L 1 -Z is independently —NH—Z; Z is independently C 6-14 carboaryl and is independently unsubstituted or substituted; R P2 is independently —H; R P5 is independently a group of the formula —W—Y; W is independently —O—; Y is independently C 6-14 carboaryl and is independently unsubstituted or substituted; and R P6 is independently —H. The present invention also pertains to pharmaceutical compositions comprising such compounds.
1 citations
Dissertation•
14 Mar 2014
TL;DR: The plaquetas desempenan un papel importante en this proceso mediante la liberacion de un numero importante de sustancias mitogenicas e inflamatorias, por lo que representan una fuente natural de FC as discussed by the authors.
Abstract: Las ulceras por presion (UPP), son lesiones de la piel cuyo origen isquemico afecta a la integridad cutanea y tejidos subyacentes, existiendo en ocasiones perdida de sustancia, que es producida por la presion prolongada o friccion entre dos planos duros, uno perteneciente al paciente y otro externo a el. El proceso de cicatrizacion de estas heridas implica la activacion de una serie de mecanismos responsables de las diferentes fases de la reparacion de los tejidos, que estan regulados por factores de crecimiento (FC), citoquinas, y factores hormonales, entre otras biomoleculas. Las plaquetas desempenan un papel importante en este proceso mediante la liberacion de un numero importante de sustancias mitogenicas e inflamatorias, por lo que representan una fuente natural de FC.
Para obtener el plasma rico en plaquetas (PRP), se extrae sangre periferica del paciente y se centrifuga, obteniendo una fraccion de plasma con una alta concentracion de plaquetas, unas 5 veces superior al numero de plaquetas basales. Esta fraccion contiene un alto contenido de biomoleculas con potencial regenerativo. Mediante su activacion con cloruro calcico se consigue su desgranulacion, obteniendo de esta forma plasma rico en factores de crecimiento (PRGF). El acido hialuronico (AH), es uno de los componentes de la matriz extracelular y esta presente en la piel, cartilago, hueso, cerebro, entre otros tejidos. Se ha demostrado su utilidad en diferentes areas clinicas, como por ejemplo, en dermatologia y neurocirugia, ya que el AH y sus productos de degradacion pueden modular la cicatrizacion de heridas.
En la presente Tesis nos planteamos dos objetivos, analizar mediante un ensayo clinico el efecto del PRGF y la asociacion PRGF y AH sobre la cicatrizacion de las UPP, asi como su relacion con las caracteristicas clinicas del paciente, y por otra parte determinar el mecanismo de actuacion del PRP mediante el estudio in vitro de su efecto sobre la capacidad proliferativa, morfologia celular y perfil antigenico de los fibroblastos humanos en cultivo.
1 citations
09 Apr 2018
TL;DR: A familial case of normosmic hypogonadotropic hypogOnadism and late puberty associated with a mutation in the FGFR1 gene is described, interesting because of pronounced phenotypic manifestations and their high concentration in the proband’s family history.
Abstract: Congenital isolated hypogonadotropic hypogonadism refers to a group of predominantly monogenic diseases associated with impaired production, secretion, and/or action of the gonadotropin-releasing hormone (GnRH), which leads to a pronounced delay or absence of puberty. Clinical and genetic heterogeneity is typical of this group of diseases. To date, about 30 candidate genes associated with the development of various forms of secondary hypogonadism are known. Congenital hypogonadotropic hypogonadism can be verified only using molecular genetic diagnostics. The correct diagnosis is necessary for predicting the disease course and choosing the proper approach for managing the patient. We describe a familial case of normosmic hypogonadotropic hypogonadism and late puberty associated with a mutation in the FGFR1 gene. The case is interesting because of pronounced phenotypic manifestations and their high concentration in the proband’s family history. Also of interest is the phenotype untypical of mutations in this gene. The molecular genetic study was performed using new generation sequencing with the authors’ panel of primers and a PGM semiconductor sequencer (Ion Torrent). The Sanger method was used to confirm the identified mutation and examine the proband’s relative. In both patients, a heterozygous mutation in the FGFR1 gene, previously described in Kallmann syndrome, was detected.
1 citations
11 Jan 2007
TL;DR: In this article, the role of FGFR4 polymorphismus im Gen der Rezeptortyrosinkinase (FGFR4) im besonderen Hinblick auf seine Zusammenhange with the humanen Tumorpathogenese naher untersucht is discussed.
Abstract: In der vorliegenden Arbeit wurde die Rolle des kurzlich identifizierten Polymorphismus im Gen der Rezeptortyrosinkinase FGFR4 (fibroblast growth factor receptor 4) im besonderen Hinblick auf seine Zusammenhange mit der humanen Tumorpathogenese naher untersucht. Es handelt sich dabei um eine Keimbahnmutation, die zu einem Austausch der hydrophoben Aminosaure Glycin gegen die hydrophile, stark geladene Aminosaure Arginin an Position 388 (Arg388) und somit zu einer veranderten Proteinstruktur in der Transmembrandomane des Rezeptors fuhrt. Zuvor publizierte Studien, die Tumore verschiedener Organsysteme mit Fokus auf den FGFR4 Polymorphismus untersuchten, postulieren einen Zusammenhang zwischen der Rezeptormutation und seinem Einfluss auf die Tumorprogression und das Metastasierungspotential. Um diesen Einfluss der Mutation in unserem Tumorkollektiv zu untersuchen, fuhrten wir bei Tumorproben von 301 Patienten, die an einem Plattenepithelkarzinom aus dem Bereich des Oropharynx litten, eine Genotypisierung mittels RFLP-PCR sowie immunhistochemische Untersuchungen durch, um die Expressionsstarke des FGFR4 feststellen zu konnen. Dabei zeigte sich, dass der FGFR4 in 34% der Falle in heterozygoter oder homozygoter mutierter Form im Kollektiv vorliegt. Das entspricht einer Allelfrequenz fur das Arg388 von 0.2. Die Verteilung der Rezeptorexpression im Kollektiv war weitgehend gleichmaβig verteilt. Um die Auswirkungen der durch die Untersuchungen gewonnenen Parameter auf die Tumorpathogenese festzustellen, wurden sie mit einem umfassenden Datensatz, der aus den Patientenakten gewonnen wurde, korreliert.
Statistische Untersuchungen wiesen keine signifikanten Zusammenhange zwischen dem FGFR4 Genotyp und der Tumorprogression oder einem gesteigertem Metastasierungspotential nach. Auch die in anderen Organsystemen zuvor festgestellte verringerte rezidivfreie Uberlebenszeit bei Vorliegen des Arg388 Allels konnte in dem Kollektiv dieser Studie nicht reproduziert werden. Bezuglich der Rezeptorexpression ergaben unsere Untersuchungen Hinweise auf einen Uberlebensvorteil bei starker FGFR4 Expression. Signifikante Zusammenhange zwischen Rezeptorexpression und Tumorgroβe oder Tumorprogression konnten jedoch nicht nachgewiesen werden und decken sich mit den Ergebnissen von Streit et al. Somit konnen wir die bereits mehrfach postulierte Perspektive nicht starken, den FGFR4 als Pradiktor oder prognostischen Parameter bei Krebserkrankungen zu deklarieren.
1 citations
01 Jan 2010
TL;DR: A large number of new cases are diagnosed each year in Sweden, and two thirds are men, and the past decades of improved treatment strate ...
Abstract: Head and neck cancer is the sixth most common cancer world wide. In Sweden approximately 850 new cases are diagnosed each year, and two thirds are men. The past decades of improved treatment strate ...
1 citations
References
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TL;DR: It is demonstrated that free heparin and heparan sulfate can reconstitute a low affinity receptor that is, in turn, required for the high affinity binding of bFGF.
2,448 citations
TL;DR: This work highlights conserved protein domains that act as key regulatory participants in many of these different signalling pathways in multicellular organisms.
Abstract: Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
2,433 citations
"Fibroblast growth factors, their re..." refers background in this paper
...One way these recruited target proteins may be localized to the activated receptor is through the interaction between their Src-homology 2 (SH2) domains and specific phosphotyrosine residues on the activated receptor (Pawson 1995)....
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...Phosphorylated tyrosine residues, in turn, recruit other signaling molecules to the activated receptors and propagate the signal through many possible transduction pathways (Pawson 1995)....
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TL;DR: Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of Thalidomid-treated embryos.
Abstract: Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
2,364 citations
TL;DR: It is demonstrated that FGF 1 is the only FGF that can activate all FGF receptor splice variants and the relative activity of all the other members of the FGF family is determined.
2,066 citations
"Fibroblast growth factors, their re..." refers background in this paper
...†From Ornitz et al. (1996), except where stated; ‡From Koga et al. (1995); §From Miralles et al. (1999); ¶From Xu et al. (1999). topologically identical to interleukin-1β (IL-1β) (Zhu et al. 1991), with which some members also share the feature of secretion by an endoplasmic reticulum…...
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...Mutation of all four cysteines to serines results in a protein with the same secondary structure and equally mitogenic for 3T3 cells as the wild-type FGF-2 (Foxet al. 1988), suggesting that the formation of disulfide bridges is not important for the secondary structure and mitogenic activity of…...
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...Ornitz et al. (1996) determined the specificity of different FGFs for different receptor isoforms by overexpressing these isoforms in Baf3 cells, which do not normally express FGFRs, and assaying for [3H]thymidine incorporation in these cells following treatment with different FGFs (see Table 2)....
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...1, IIIb 100 60 34 16 4 5 6 4 4 1, IIIc 100 104 0 102 59 55 0 1 21 2, IIIb 100 9 45 15 5 5 81 4 7 2, IIIc 100 64 4 94 25 61 2.5 16 89 3, IIIb 100 1 2 1 1 1 1 1 42 3, IIIc 100 107 1 69 12 9 1 41 96 4 100 113 6 108 7 79 2 76 75 Modified from Ornitz et al. (1996)....
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1,994 citations
"Fibroblast growth factors, their re..." refers background in this paper
...Defining features of the FGF family are a strong affinity for heparin and HLGAGs (Burgess & Maciag 1989), as well as a central core of 140 amino acids that is highly homologous between different family members....
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