High molecular weight Fibroblast Growth Factor 2 (FGF2) requires an active Fibroblast Growth Factor Receptor 1 (FGFR1) to depress post‐ischemic cardiac function
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Fibroblast growth factor 2 (FGF2) is a family of isoforms with potential both as therapeutic molecules, as well as endogenous targets for pharmacological modulation in cardiac ischemia. Our laboratory has previously demonstrated that the secreted low moledular weight (LMW) FGF2 isoform protects the heart against myocardial dysfunction induced by ischemia‐reperfusion (I/R) injury by activating the FGF receptor 1 (FGFR1), while the mechanisms by which the high molecular weight (HMW) FGF2 isoforms produce the opposing and detrimental effects on cardiac function following I/R are less clear. The purpose of this study was to examine whether FGFR1 activation is necessary for the effects of HMW FGF2. Using an isolated work‐perfoming heart model, mice overexpressing the 24kDa isoform of FGF2 were subjected to global low‐flow ischemia in the presence of an inhibitor to FGFR1. The blockade of FGFR1 resulted in higher post‐ischemic contractility in transgenic hearts (p<0.05). We also found differences in the activation of kinases downstream from FGFR1, including protein kinase C (PKC) and mitogen activated protein kinases (MAPKs), indicating that HMW FGF2 alters the targets of FGFR1 signaling cascades. These findings indicate that HMW FGF2 mediates its effects by modulating FGFR1 signaling, to induce post‐ischemic myocardial dysfunction. Research supported by NIH grant NIH/NHLBI RO1 HL075633Keywords:
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Dysregulation of fibroblast growth factor (FGF) signaling in renal cell carcinoma is now well understood, and it is becoming increasingly likely that certain tumors become dependent on an activation of this pathway for their growth and survival. Dissecting the FGF/FGF receptor (FGFR) pathway offers the hope of developing new therapeutic approaches that selectively target the FGF/FGFR axis in patients whose tumors are known to harbor FGF/FGFR dysregulation. In this review, we summarize the existing data on the role of FGFR1 in the pathogenesis of renal cell carcinoma and discuss methodological issues for drug investigation in this setting.
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Basic fibroblast growth factor (FGF2, bFGF) is the most extensively studied member of the FGF family and is involved in neurogenesis, differentiation, neuroprotection, and synaptic plasticity in the CNS. FGF2 executes its pleiotropic biologic actions by binding, dimerizing, and activating FGF receptors (FGFRs). The present study reports the physiologic impact of various FGF2-FGFR1 contact sites employing three different synthetic peptides, termed canofins, designed based on structural analysis of the interactions between FGF2 and FGFR1. Canofins mimic the cognate ligand interaction with the receptor and preserve the neuritogenic and neuroprotective properties of FGF2. Canofins were shown by surface plasmon resonance analysis to bind to FGFR1 and promote receptor activation. However, FGF2-induced receptor phosphorylation was inhibited by canofins, indicating that canofins are partial FGFR agonists. Furthermore, canofins were demonstrated to induce neuronal differentiation determined by neurite outgrowth from cerebellar granule neurons, and this effect was dependent on FGFR activation. Additionally, canofins acted as neuroprotectants, promoting survival of cerebellar granule neurons induced to undergo apoptosis. Our results suggest that canofins mirror the effect of specific interaction sites in FGF2 for FGFR. Thus, canofins are valuable pharmacological tools to study the functional roles of specific molecular interactions of FGF2 with FGFR.
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Although the detection of several components of the fibroblast growth factor (FGF) signaling pathway in human embryonic stem cells (hESCs) has been reported, the functionality of that pathway and effects on cell fate decisions are yet to be established. In this study we characterized expression of FGF-2, the prototypic member of the FGF family, and its receptors (FGFRs) in undifferentiated and differentiating hESCs; subsequently, we analyzed the effects of FGF-2 on hESCs, acting as both exogenous and endogenous factors. We have determined that undifferentiated hESCs are abundant in several molecular-mass isoforms of FGF-2 and that expression pattern of these isoforms remains unchanged under conditions that induce hESC differentiation. Significantly, FGF-2 is released by hESCs into the medium, suggesting an autocrine activity. Expression of FGFRs in undifferentiated hESCs follows a specific pattern, with FGFR1 being the most abundant species and other receptors showing lower expression in the following order: FGFR1 --> FGFR3 --> FGFR4 --> FGFR2. Initiation of differentiation is accompanied by profound changes in FGFR expression, particularly the upregulation of FGFR1. When hESCs are exposed to exogenous FGF-2, extracellular signal-regulated kinases are phosphorylated and thereby activated. However, the presence or absence of exogenous FGF-2 does not significantly affect the proliferation of hESCs. Instead, increased concentration of exogenous FGF-2 leads to reduced outgrowth of hESC colonies with time in culture. Finally, the inhibitor of FGFRs, SU5402, was used to ascertain whether FGF-2 that is released by hESCs exerts its activities via autocrine pathways. Strikingly, the resultant inhibition of FGFR suppresses activation of downstream protein kinases and causes rapid cell differentiation, suggesting an involvement of autocrine FGF signals in the maintenance of proliferating hESCs in the undifferentiated state. In conclusion from our data, we propose that this endogenous FGF signaling pathway can be implicated in self-renewal or differentiation of hESCs.
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Fibroblast growth factors may play an important role in the differential growth of the skull, brain, and facial prominences. In order to understand the role of FGFs in vivo, we have analyzed the competency of head mesenchyme to respond to FGFs via expression of the high affinity receptors FGFR1, 2, and 3. Receptor transcripts, especially those of FGFR2 and FGFR3, were localized to specific regions of the head. We raise the possibilities of particular receptor-ligand combinations and the possible functions of these interactions in the morphogenesis of the head, face, and brain. Finally, we discuss the relationship between FGF receptor expression in the chicken and the phenotypes of FGF receptor mutations in humans. Dev. Dyn. 1997; 210:41–52. © 1997 Wiley-Liss, Inc.
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