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At least 235 records · Page 13Linked to original sources
PubMed2001

Developmental expression of fibroblast growth factor (FGF) receptors in neural stem cell progeny. Modulation of neuronal and glial lineages by basic FGF treatment.

Neural stem cells (NSCs) are self-renewable, multipotential cells capable of differentiating into the three major neural cell types, but the mechanisms which regulate their development are not fully understood. Both basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) promote the proliferation of NSCs. However, studies on the role of FGFs in the differentiation of EGF-expanded NSCs are still incomplete. We have studied the expression of distinct FGF receptors (FGFRs) in the progeny of EGF-expanded NSCs isolated from E15 rat striatum. In situ hybridization analysis and immunocytochemistry showed a developmentally related expression pattern and a cell lineage-specific distribution of these receptors. FGFR1 and FGFR2 were identified in many early precursors and in the oligodendrocyte lineage. The latter receptor was also present in a subpopulation of astrocytes. FGFR3 was detected in a restricted population of early precursors, in oligodendroglial progenitors, and in neurons and protoplasmic astrocytes of late-term cultures. Basic FGF treatment of the progeny of NSCs increased the proliferative rate of precursors and the number of oligodendrocytes generated, whereas the number of differentiating neurons was significantly reduced. Together these data provide evidence that FGFs modulate the development of EGF-expanded NSCs, and that this is at least partly determined by a cell lineage-specific expression of multiple FGFRs.

Animals↗
PubMed1995

Identification of fibroblast growth factor 9 (FGF9) as a high affinity, heparin dependent ligand for FGF receptors 3 and 2 but not for FGF receptors 1 and 4.

Fibroblast growth factors (FGF) are multifunctional, heparin binding polypeptides that share structural similarity, but differ in their target cell specificity and expression pattern. Here we describe the cloning and expression of the mouse homologue of FGF9, and the use of a panel of soluble FGF receptors and genetically engineered cells to study its receptor binding specificity. FGF9 is found to bind with high affinity (kd: 0.25 nM) to FGFR3, for which a specific ligand has not yet been identified. FGF9 can also bind, albeit with a lower affinity, to FGFR2 but does not bind FGFR1 or FGFR4. There is no significant binding to either FGFR3 or FGFR2, expressed either as soluble receptors or in heparin sulfate deficient cells, in the absence of heparin. Moreover, receptor binding of FGF9 requires heparin in a manner specific to the receptor type. In conclusion FGF9 presents a unique case of ligand-receptor specificity and fulfills the criteria as a high affinity, heparin-dependent ligand for FGFR3.

Amino Acid Sequence↗
PubMed2007

Ovine endometrial expression of fibroblast growth factor (FGF) 2 and conceptus expression of FGF receptors during early pregnancy.

In ruminants, conceptus development beyond the blastocyst state requires input from uterine-derived factors. Fibroblast growth factor 2 (FGF2) is expressed by the bovine endometrium throughout the estrus cycle and early pregnancy and stimulates trophectoderm expression of interferon-tau, the maternal recognition of pregnancy factor in ruminants. The objective of this study was to examine the expression of FGF2 in ovine endometrium and peri-attachment conceptuses and FGF receptors (FGFR) in conceptuses. FGF2 mRNA was present in the ovine endometrium with specific localization within the luminal and glandular epithelium. No pregnancy-dependent changes in endometrial FGF2 mRNA abundance were detected until placental attachment was well underway. FGF2 protein was detected in the uterine lumen throughout the estrous cycle and early pregnancy. Concentrations of luminal FGF2 protein did not differ based on pregnancy status. However, uterine luminal FGF2 protein levels increased at days 12-13 after estrus in both cyclic and pregnant ewes. Ovine conceptuses collected at days 14-19 after mating contained transcripts for FGF2 and FGFR types 1, 2 and 3. In summary, FGF2 is expressed by the ovine endometrium and conceptus during early pregnancy, and peri-attachment conceptuses possess several FGFR types. Concentrations of FGF2 protein in the uterine lumen increase coincident with the initiation of pregnancy recognition in ewes. These observations support the concept that FGF2 and potentially other FGFs may affect conceptus development and/or gene expression during early pregnancy in ruminants.

Animals↗
PubMed1990

Effect of heparin on the binding affinity of acidic FGF for the cloned human FGF receptors, flg and bek.

Heparin potentiates the mitogenic activity of acidic fibroblast growth factor (aFGF) by 20-100 fold but mechanisms detailing this potentiation have not yet been fully elucidated. We report that heparin increases the binding affinity of aFGF for the two cloned and overexpressed human FGF receptors, flg and bek, by 2-3 fold. This increase in binding affinity, together with previous data demonstrating a 3-5 fold increase in the stability of aFGF, are likely to account for a significant portion of heparin's potentiation of aFGF activity observed in biological assay systems.

Animals↗
PubMed1997

Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs.

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.

3T3 Cells↗
PubMed2004

FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development.

beta-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize beta-catenin result in augmented gene transcription and play a major role in many human cancers. We employed microarrays to identify transcriptional targets of deregulated beta-catenin in a human epithelial cell line (293) engineered to produce mutant beta-catenin and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/beta-catenin pathway. Two genes strongly induced in both systems-FGF20 and DKK1-were studied in detail. Elevated levels of FGF20 RNA were also observed in adenomas from mice carrying the Apc(Min)allele. Both XFGF20 and Xdkk-1 are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. Furthermore, FGF20 and DKK1 appear to be direct targets for beta-catenin/TCF transcriptional regulation via LEF/TCF-binding sites. Finally, by using small inhibitory RNAs specific for FGF20, we show that continued expression of FGF20 is necessary for maintenance of the anchorage-independent growth state in RK3E cells transformed by beta-catenin, implying that FGF-20 may be a critical element in oncogenesis induced by the Wnt signaling pathway.

Adenocarcinoma↗
PubMed2001

Selective inhibition of fibroblast growth factor (FGF)-stimulated mitogenesis by a FGF receptor-1-derived phosphopeptide.

The activated fibroblast growth factor receptor (FGFR)-1 is phosphorylated on five tyrosine residues outside the catalytic site. Although one such residue, Tyr730, is flanked by potential binding sites for phosphotyrosine-interacting molecules, a physiological role for this region is still controversial. We report that a cell-permeant phosphopeptide mimic of this site, FGFR730(p)Y, inhibits FGF-mediated mitogenesis in cells with no effect on responses stimulated by other growth factors. A similar phosphopeptide corresponding to the phospholipase Cgamma binding site on the receptor had no effect on the mitogenic response. The FGFR730(p)Y peptide did not inhibit phosphorylation of p90/FRS2 or Erk, suggesting that it does not act by inhibiting the Erk-kinase cascade. However, the FGFR730(p)Y peptide bound Shc in a manner requiring both phosphorylated tyrosine and a putative PTB domain binding determinant. These data suggest that the peptide might inhibit mitogenesis by competing with the corresponding site on the FGFR for the ability to bind SHC.

3T3 Cells↗
PubMed2001

Expression of the IIIc Variant of FGF Receptor-1 Confers Mitogenic Responsiveness to Heparin and FGF-5 in TAKA-1 Pancreatic Ductal Cells.

Human pancreatic cancer is a devastating diseasewith a poor prognosis (1). Although the exact reasonsfor the aggressive nature of this disorder are unknown, certain observations have pointed to theimportant role of growth factors in its pathobiology(2). Many of these cancers frequently overexpressfibroblast growth factors (FGFs) (3). FGF signalingis mediated through four high-affinity tyrosine kinasereceptors, termed fibroblast growth-factor receptors(FGFRs) (3,4). The extracellular domain of FGFRsis usually composed of three immunoglobulin (Ig)-like domains (I-III), a transmembrane region followedby a juxtamembrane domain, and a splittyrosine kinase catalytic domain. Several isoformsof FGFR-1, -2, and -3 have been identified, some of which exhibit different ligand-binding properties(3,5). Alternative splicing of the second half of Igdomain III of FGFR-1 results in three receptor variants,termed IIIa, IIIb, and IIIc. The IIIa splice variantyields a secreted receptor that is devoid of anysignaling capacity (5). The expression of the IIIbvariant is generally restricted to epithelial cell types,whereas the expression of the IIIc variant is restrictedto mesenchymal cell types (6-11).

Journal Article↗
PubMed1992

Positive and negative control of the skeletal alpha-actin promoter in cardiac muscle. A proximal serum response element is sufficient for induction by basic fibroblast growth factor (FGF) but not for inhibition by acidic FGF.

Like mechanical load in vivo, basic fibroblast growth factor (bFGF) selectively provokes cardiac expression of "fetal" genes including skeletal alpha-actin (SkA). Antithetically, acidic FGF (aFGF) suppresses SkA transcription. To define sites controlling SkA transcription in cardiac muscle cells, rat cardiac myocytes were transfected with internal-deletion and block-substitution mutations in the SkA promoter, including three motifs resembling the fos serum response element (SRE). The upstream, central, and proximal SREs each contributed to basal expression in cardiac myocytes. To determine whether identical elements mediate induction by bFGF versus inhibition by aFGF, the proximal SRE (SRE1) and fos SRE were positioned upstream from a neutral promoter. In cardiac myocytes, both the SRE1 and fos SRE were expressed at levels up to one-third that of the SkA promoter (nucleotides -202 to -11). Neither was expressed in quiescent cardiac fibroblasts. bFGF augmented SRE1-CAT activity, whereas aFGF produced no change; the fos SRE was induced by both. The transcriptional and mitogenic actions of aFGF were contingent on the presence of a putative nuclear translocation motif. Thus 1) the SkA SRE1 and fos SRE each suffice for tissue specificity in cardiac myocytes; 2) unlike the c-fos SRE, the SkA SRE1 is induced selectively by bFGF yet not aFGF; 3) sequences alternative or in addition to the SRE1 are obligatory for aFGF to suppress the SkA promoter; and 4) possible differences in intracellular localization are one basis for divergent actions of aFGF and bFGF in cardiac muscle cells.

Actins↗
PubMed1996

CAM-FGF receptor interactions: a model for axonal growth.

A number of experimental paradigms have been used to demonstrate that NCAM, N-cadherin, and L1 stimulate axonal growth. The molecular basis of this response has been extensively studied and a range of agents that inhibit neurite outgrowth stimulated by the above CAMs, but not integrins, have now been identified. These studies pointed to the activation of a tyrosine kinase-PLCgamma cascade as being important for the neurite outgrowth responses stimulated by all three CAMs, and this was substantiated by the identification of agents that could activate the cascade and mimic the growth response. In this review we will suggest that the neurite growth response stimulated by these CAMs is mediated by activation of the fibroblast growth factor receptor (FGFR) in neurons and that this results in the recruitment and activation of PLCgamma via interactions of its SH2 domain with the activated receptor. In this context the key events downstream from activation of PLCgamma required for neurite growth appear to be the conversion of diacylglycerol (DAG) to arachidonic acid (AA) via DAG lipase activity, followed by an increased influx of calcium into the neurons. The evolutionary conservation of putative binding motifs between the above CAMs and the FGFR suggests that activation of the FGFR-PLCgamma cascade by the CAMs might involve a direct CAM-FGFR interaction. The identification of the binding motifs also allows for predictions to be made concerning whether other CAMs might directly interact with the FGFR.

Amino Acid Sequence↗
PubMed2003

Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.

Identical proline-->arginine gain-of-function mutations in fibroblast growth factor receptor (FGFR) 1 (Pro252Arg), FGFR2 (Pro253Arg) and FGFR3 (Pro250Arg), result in type I Pfeiffer, Apert and Muenke craniosynostosis syndromes, respectively. Here, we characterize the effects of proline-->arginine mutations in FGFR1c and FGFR3c on ligand binding using surface plasmon resonance and X-ray crystallography. Both Pro252Arg FGFR1c and Pro250Arg FGFR3c exhibit an enhancement in ligand binding in comparison to their respective wild-type receptors. Interestingly, binding of both mutant receptors to FGF9 was notably enhanced and implicates FGF9 as a potential pathophysiological ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure, of Pro252Arg FGFR1c in complex with FGF2, demonstrates that the enhanced ligand binding is due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the Apert syndrome Pro253Arg FGFR2c-FGF2 crystal structure. However, unlike the Apert syndrome Pro253Arg FGFR2c mutant, neither the Pfeiffer syndrome Pro250Arg FGFR1c mutant nor the Muenke syndrome Pro250Arg FGFR3c mutant bound appreciably to FGF7 or FGF10. This observation provides a potential explanation for why the limb phenotypes, observed in type I Pfeiffer and Muenke syndromes, are less severe than the limb abnormalities observed in Apert syndrome. Hence, although analogous proline-->arginine mutations in FGFR1-3 act through a common structural mechanism to result in gain-of-function, differences in the primary sequence among FGFRs result in varying effects on ligand binding specificity.

Amino Acids↗
PubMed2003

Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth.

Human craniosynostosis syndromes, resulting from activating or neomorphic mutations in fibroblast growth factor receptor 2 (FGFR2), underscore an essential role for FGFR2 signaling in skeletal development. Embryos harboring homozygous null mutations in FGFR2 die prior to skeletogenesis. To address the role of FGFR2 in normal bone development, a conditional gene deletion approach was adopted. Homologous introduction of cre recombinase into the Dermo1 (Twist2) gene locus resulted in robust expression of CRE in mesenchymal condensations giving rise to both osteoblast and chondrocyte lineages. Inactivation of a floxed Fgfr2 allele with Dermo1-cre resulted in mice with skeletal dwarfism and decreased bone density. Although differentiation of the osteoblast lineage was not disturbed, the proliferation of osteoprogenitors and the anabolic function of mature osteoblasts were severely affected.

Animals↗
PubMed2001

Expression of basic fibroblast growth factor (bFGF), FGF receptor 1 and FGF receptor 2 in uterine leiomyomas and myometrium during the menstrual cycle, after menopause and GnRHa treatment.

BACKGROUND: To investigate whether basic fibroblast growth factor (bFGF) is involved in the growth regulation of human uterine leiomyomas the expression of bFGF and its receptors was measured in leiomyomas and myometrium obtained under different endocrine conditions. METHODS: The expression of bFGF, fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor 2 (FGFR2) was analyzed by immunohistochemistry and Western blot. RESULTS: Twenty-seven women with leiomyomas included eight in the proliferative phase, seven in the secretory phase, six after menopause and six after GnRHa treatment. In the proliferative phase, bFGF staining in leiomyomas was significantly stronger than in any other leiomyoma group. After GnRHa treatment, the expression of bFGF in both leiomyomas and myometrium was weaker than in the proliferative phase. The staining of FGFR1 was less intense in proliferative phase myometrium than in myometrium from any other group, significantly weaker than in the secretory phase. The leiomyomas demonstrated homogeneous cytoplasmic FGFR1 staining that was similar in all groups, except in the GnRHa treated patients where a more intense staining was observed, significantly stronger than in proliferative phase leiomyomas. No tissue differences were observed for staining of FGFR2 and no significant differences were observed between the different groups. Slightly less staining of FGFR2 was found in leiomyomas in the secretory phase but it did not reach statistical significance. The specificity of immunostaining was confirmed by Western blot. CONCLUSIONS: We suggest that the regulation of bFGF, and to some extent also its receptors in leiomyomas and in myometrium, is influenced by sex steroid hormones. However, the lack of differences in expression between leiomyomas and myometrium favors the view that bFGF does not necessarily contribute to the differences in growth regulation in these tissues.

Adult↗