人成纤维细胞生长因子受体2的研究进展

人成纤维细胞生长因子受体 (FGFRs)家族在细胞的增殖、分化、血管生成、胚胎及骨骼发育和在与生长发育相关的进程中起着十分重要的作用。成纤维细胞生长因子受体 2 (FGFR2 )是该家族 4个成员中的一员 ,本文就其结构特点及与骨骼发育、肿瘤形成和其他疾病的关系加以综述     

FGFR2基因与乳腺癌的相关性研究

成纤维细胞生长因子受体 2 (FGFR2 )是人成纤维细胞生长因子受体(FGFR s) 家族中的一员，其结构特点与肿瘤形成，骨骼发育及其他疾病的发生有密切关系，研究表明成纤维细胞生长因子受体2（FGFR2)的基因多态性与乳腺癌的发生存在一定相关性。本文就其特点作如下总结．     

成纤维细胞生长因子受体3在软骨发育分化过程中的意义

成纤维细胞生长因子(fibroblast growth factor，FGF)是一组结构相似的多肽类家族，目前已发现有19个成员，其在胚胎发育、血管新生、伤口愈合、肿瘤形成中发挥重要作用。这些作用的发挥是通过与其细胞表面受体相结合后而介导的。目前已克隆出4种成纤维细胞生长因子受体(fibroblast growth factor receptor，FGFR)，虽然4种FGFRs结构相似，但每种FGFR在机体发育的不同阶段及不同组织中各有其特殊的表达方式。近来研究证明，在软骨和骨的发育分化过程中，FGFR3发挥着重要的作用，我们对此进行综述。     

脊椎动物成纤维细胞生长因子及其受体

成纤维细胞生长因子(FGFs)具有广泛的生物学功能,已知FGF家族至少包括23个因子(FGFs1-23);成纤维细胞生长因子受体(FGFRs)家族有3类:酪氨酸激酶受体类、富胱氨酸FGF受体和低亲和力受体肝素硫酸糖蛋白。FGFs和FGFRs一起组成了一个大而复杂的信号分子家族,具有促细胞分裂、促细胞运动和促形态形成的作用,在胚胎、组织发育和成熟中发挥着重要作用。     

FGFs/FGFRs信号传递的研究进展

成纤维细胞生长因子(FGFs)和成纤维细胞生长因子受体(FGFRs)所形成的信号传递通路与疾病有着密切的关系。对阻断其信号传递的研究已成为治疗疾病和药物开发的新靶点。本文就FGFs/FGFRs信号传递及与疾病关系的研究进展进行了综述。     

FGF10及其受体FGFR1、FGFR2在昆明小鼠输卵管和子宫内的分布

目的观察成纤维细胞生长因子10(FGF10)、成纤维细胞生长因子受体(FGFR1、FGFR2)在昆明小鼠输卵管和子宫内的定位与分布。方法应用免疫组织化学法进行蛋白质定位观察。结果FGF10和FGFR1免疫阳性反应定位于昆明小鼠输卵管上皮细胞,FGFR2的免疫阳性反应见于肌层平滑肌。FGF10和FGFR1免疫阳性反应分布于昆明小鼠子宫内膜上皮、子宫腺上皮和肌层平滑肌,而FGFR2免疫阳性反应见于肌层平滑肌。结论FGF10及其受体在输卵管和子宫的分布可能参与输卵管和子宫的重要功能。     

FGFS/FGFRS在骨骼发育与疾病中的作用

成纤维细胞生长因子 (fibroblast growth factors,FGFs)及其受体成纤维细胞生长因子受体 (fibroblast growthfactor receptors,FGFRs)在许多组织、器官的发育和疾病发生、发展过程中有重要作用。现代分子生物、分子遗传技术包括转基因和基因敲除技术等的应用极大地加深了对 FGFs、FGFRs的结构和功能 ,尤其是它们在人体遗传性骨骼疾病 (侏儒和囟门早闭 )中作用和机制的认识。本综述将介绍 FGFS/ FGFRS在骨骼发育与疾病中的作用。     

FGFS／FGFRS在骨骼发育与疾病中的作用

成纤维细胞生长因子(fibroblast growth factors．FGFs)及其受体成纤维细胞生长因子受体(fibroblast growth factor receptors,FGFRs)在许多组织、器官的发育和疾病发生、发展过程中有重要作用。现代分子生物、分子遗传技术包括转基因和基因敲除技术等的应用极大地加深了对FGFs、FGFRs的结构和功能，尤其是它们在人体遗传性骨骼疾病(侏儒和囟门早闭)中作用和机制的认识。本综述将介绍FGFS／FGFRS在骨骼发育与疾病中的作用。     

成纤维细胞生长因子受体-1、2和3在昆明小鼠卵母细胞和植入前胚中的表达与分布

目的:观察成纤维细胞生长因子受体(FGFR)-1、2和3在昆明小鼠卵母细胞和植入前胚中的表达和分布,为进一步探讨成纤维细胞生长因子(FGF)对昆明小鼠卵母细胞和植入前胚发育的影响提供实验依据.方法:逆转录-聚合酶链式反应(RT-PCR)、免疫荧光细胞化学显色和共聚焦扫描显微镜观察.结果:RT-PCR检测显示,FGFR1、FGFR2和FGFR3 mRNA在昆明小鼠卵母细胞和植入前胚均有表达;免疫荧光细胞化学显色、共聚焦扫描显微镜观察显示FGFR1、FGFR3免疫阳性反应见于卵母细胞和植入前胚胞质周边,靠近细胞膜;FGFR2阳性反应较均匀分布于卵母细胞和植入前胚的胞质.结论:FGFR1、FGFR2、FGFR3在小鼠卵母细胞和植入前胚发育的不同阶段都有表达,可能介导FGF调节小鼠卵母细胞和植入前胚的发育.     

FGFR3在骨骼发育和疾病中作用的研究进展

FGFR3是成纤维细胞生长因子受体（Fibroblast growth factor receptors ,FGFRs）家族成员之一,在骨骼发育中起重要作用。FGFR3的激活突变引起一系列骨骼发育缺陷性疾病,如软骨发育不全（achondroplasia,ACH）、季肋发育不全（hypochondroplasia,HCH）和致死性骨发育不全（thanatophoric dysplasia,TD）。目前研究认为,FGFR3在骨骼发育中抑制软骨形成的作用是明确的,但其对骨形成的作用尚不明确,需要进一步研究。     

Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma

Fibroblast growth factor receptor 2 is a member of receptor tyrosine kinase family, and fibroblast growth factor receptor 2 gene amplification or missense mutation has been observed in various human cancers, including gastric carcinoma. Recent studies have shown that anti-fibroblast growth factor receptor 2 agents inhibit tumor progression in various human cancers, such as endometrial carcinoma and gastric carcinoma, which remains one of the most frequent causes of cancer-related death worldwide. We considered that knowledge of the status of fibroblast growth factor receptor 2 gene amplification in gastric carcinoma might aid in targeted cancer therapy. In this study, fibroblast growth factor receptor 2 amplification status was evaluated by fluorescence in situ hybridization in 313 surgically resected gastric carcinoma tissues, and the results were validated by quantitative real-time polymerase chain reaction. In addition, potential associations between clinicopathologic parameters and the presence of fibroblast growth factor receptor 2 amplification were investigated, and survival analysis was performed. Of the 313 cases, 14 (4.5%) showed fibroblast growth factor receptor 2 amplification by fluorescence in situ hybridization. Fibroblast growth factor receptor 2 amplification was found to be associated with a higher pT stage (P = .023), higher pN stage (P = .038), and distant metastasis (P = .009) and to be significantly associated with lower cancer-specific survival by univariate analysis (P = .012). Gastric carcinoma with fibroblast growth factor receptor 2 amplification was found to be associated with advanced disease and a poor prognosis. We believe that the determination of fibroblast growth factor receptor 2 amplification status could allow the identification of a subset of cancers sensitive to targeted fibroblast growth factor receptor 2 inhibitor-based therapy.     

酸性成纤维细胞生长因子促进大鼠肠缺血-再灌注损伤的修复

背景：细胞外调节蛋白激酶和酸性成纤维细胞生长因子受体2在肠缺血-再灌注损伤修复中的作用尚无研究报道。 目的：观察大鼠肠缺血-再灌注损伤后外源性酸性成纤维细胞生长因子对细胞外调节蛋白激酶和酸性成纤维细胞生长因子受体2表达的影响,探讨细胞外调节蛋白激酶和酸性成纤维细胞生长因子受体2与酸性成纤维细胞生长因子促进创伤修复的关系。 方法：以大鼠肠系膜上动脉夹闭45 min造成肠缺血-再灌注损伤模型,于再灌注即刻应用酸性成纤维细胞生长因子行干预。分别于再灌注2,6,12,24 h取大鼠小肠组织标本,利用免疫组化和RT-PCR检测酸性成纤维细胞生长因子受体的表达及免疫组化检测细胞外调节蛋白激酶表达的规律。 结果与结论：在正常大鼠,酸性成纤维细胞生长因子受体2主要分布在小肠绒毛上皮细胞的肠腔侧、侧壁和小肠隐窝朝向隐窝腔的一侧细胞膜上。缺血-再灌注初期,酸性成纤维细胞生长因子受体2及细胞外调节蛋白激酶的表达未发生明显变化,但随着再灌注时间的延长表达水平逐渐提高,并于再灌注后6-12 h达高峰。经酸性成纤维细胞生长因子治疗后,大鼠小肠组织小肠黏膜损伤程度减轻,酸性成纤维细胞生长因子受体2及细胞外调节蛋白激酶的表达量高于未治疗大鼠。结果表明缺血-再灌注损伤后,酸性成纤维细胞生长因子干预可上调酸性成纤维细胞生长因子受体2及细胞外调节蛋白激酶的表达,提示外源性酸性成纤维细胞生长因子通过促进内源性酸性成纤维细胞生长因子受体2和细胞外调节蛋白激酶的生成可能是其参与内脏损伤修复的机制之一。     

Age-related changes in levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2 in the rat inferior colliculus: implications for neural senescence

Brain-derived neurotrophic factor and fibroblast growth factor 2, and their respective binding sites, tyrosine kinase B receptor and fibroblast growth factor receptor 2, are known to regulate neurite outgrowth and antioxidant enzyme activity. Several studies suggest that brain-derived neurotrophic factor and fibroblast growth factor are contained in the inferior colliculus. Previous work in our laboratories revealed dendritic and synaptic losses in the inferior colliculus of aged Fischer-344 rats, along with coincident increases in lipid peroxidation possibly linked to a decrease in activity of antioxidant enzymes. In an effort to identify potential causal mechanisms underlying age-related synaptic and dendritic losses that occur in the inferior colliculus, the present study attempted to determine if inferior colliculus levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2 expression are altered with age.Immunocytochemistry was performed in the inferior colliculus, hippocampus and cerebellum of 3-month-old F344 rats to study distributions of the full-length and truncated isoforms of tyrosine kinase B receptor, and fibroblast growth factor receptor 2. The latter two brain regions served as positive controls. For all three antigens, immunolabeling was localized primarily in somata and proximal dendrites in all subdivisions of the inferior colliculus, and in the dentate gyrus and Ammon's horn of the hippocampus. In the cerebellum, the somata and dendrites of the Purkinje cells were also immunolabeled.A significant reduction in levels of the full-length form of tyrosine kinase B receptor in 18- and 25-month-old rats (respectively, approximately 20% and 30% relative to 3-month-olds) was revealed using western blot analyses. Inferior colliculus and hippocampal levels of the truncated form were modestly decreased ( approximately 7%) as well in the two older age groups. In contrast, levels of fibroblast growth factor receptor 2 in the inferior colliculus and hippocampus were elevated by approximately 35% in the two older age groups when compared to 3-month-olds. Changes in cerebellar levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2, while similar to those in the inferior colliculus and hippocampus among the age groups, did not achieve statistical significance in this study.These findings give rise to the possibility that age-related reductions in tyrosine kinase B receptor levels could be a causal factor in the degenerative changes observed in the inferior colliculus of aged animals, including mitochondrial damage and dendritic regression. The observed increases in fibroblast growth factor receptor 2 levels may be compensatory to the increased oxidative stress. The effectiveness of the fibroblast growth factor receptor 2 response is questionable given the damage that occurs in the inferior colliculus and hippocampus of aged animals. However, the deficits could worsen in the absence of an increase in fibroblast growth factor receptor 2.     

Transient lesion-induced increase of basic fibroblast growth factor and its receptor in layer VIb (subplate cells) of the adult rat cerebral cortex.

Basic fibroblast growth factor is a potent trophic factor with a wide spectrum of activity at various stages of neuronal development. In our studies on the effects of select lesions on the expression of growth factors, we observed that neurons of layer VIb of the rat cerebral cortex developed immunoreactivity for basic fibroblast growth factor and its receptor following injury. Recent evidence indicates that layer VIb of the rat cerebral cortex contains the subplate cell population, a group of neurons shown to participate in the development of the cerebral cortex. In this article, we examined the nature and time-course of the response to injury of the expression of basic fibroblast growth factor and its receptor in these cells. We used an anti-basic fibroblast growth factor monoclonal antibody that recognizes the active form of basic fibroblast growth factor, and a polyclonal antibody that recognizes the extracellular domain of the basic fibroblast growth factor receptor. The induction of basic fibroblast growth factor and its receptor in layer VIb cells occurred after entorhinal cortex lesion, fimbria-formix transection or aspiration of small segment of the frontoparietal cortex. The lesion-induced effect was transient, appearing by postlesion day 2 and having disappeared by postlesion day 7. These findings suggest that endogenous basic fibroblast growth factor may have a neuroprotective role on layer VIb neurons after trauma and/or may participate in cortical plasticity during adulthood.     

Immunochemical evidence for a fibroblast growth factor receptor in adult retinal optic fiber and synaptic layers

Evidence for fibroblast growth factor receptors in the central nervous system has only been obtained using autoradiographic localization of fibroblast growth factor binding sites and messenger RNA. To clarify those neuronal functions that are regulated by fibroblast growth factor receptors, we have localized immunocytochemically the fibroblast growth factor receptor protein in bovine retina, a neural tissue of well-defined structure and function. The extracellular domain of the gene product referred to as fibroblast growth factor receptor 2 was expressed genetically in bacteria to obtain a polyclonal antibody. Positive staining was confined almost exclusively to the synaptic and optic fiber layers.

Such a specific association suggests a role for this receptor in modulation of synaptic terminals and ganglion cell axons of the optic nerve, especially with respect to glutamate release.     

Visual input regulates the expression of basic fibroblast growth factor and its receptor.

Emerging evidence indicates that the expression of trophic factors in the brain is regulated in an activity-dependent manner, which suggests an involvement of trophic factors in events controlled by input activity. We have investigated the possibility that visual sensory input impacts the expression of basic fibroblast growth factor and its receptor in the brain. Rats were maintained for seven days in darkness and then re-exposed to normal illumination for 0, 1, 3 or 6 h. We assessed relative levels of basic fibroblast growth factor and fibroblast growth factor receptor messenger RNAs using nuclease protection assays, and examined possible changes in the phenotypic expression of basic fibroblast growth factor and its receptor using immunohistochemistry. There was a significant decrease in levels of basic fibroblast growth factor and fibroblast growth factor receptor messenger RNAs as a result of dark rearing, and levels of messenger RNAs increased progressively with light re-exposure. Changes in messenger RNAs were observed primarily in the cerebral cortex (caudal portion) and were accompanied by alterations in the staining intensity and density of cells exhibiting basic fibroblast growth factor and fibroblast growth factor receptor phenotypes. Regulation of the basic fibroblast growth factor system by sensory input suggests that basic fibroblast growth factor, and perhaps other trophic factors, are mediators of the effects of experience on the structure and function of the CNS.     

外源性酸性成纤维细胞生长因子干预肠缺血-再灌注损伤中p38MAPK和成纤维细胞生长因子受体2的表达

背景：酸性成纤维细胞生长因子可以促进多种创面愈合,在内脏损伤修复中起重要促进作用。 目的：观察外源性酸性成纤维细胞生长因子干预肠缺血-再灌注损伤大鼠后p38MAPK和成纤维细胞生长因子受体2的表达。 方法：以大鼠肠系膜上动脉夹闭45 min造成肠缺血-再灌注损伤模型,于再灌注即刻应用改构体酸性成纤维细胞生长因子进行干预。分别于再灌注2,6,12,24 h取大鼠小肠组织标本,用于实验。 结果与结论：在正常大鼠,成纤维细胞生长因子受体2主要分布在小肠绒毛上皮细胞的肠腔侧、侧壁和小肠隐窝朝向隐窝腔的一侧细胞膜上。缺血-再灌注初期,p38MAPK蛋白及成纤维细胞生长因子受体2蛋白和mRNA的表达未发生明显变化,随着再灌注时间的延长其逐渐增强,并于再灌注后6~12 h达高峰。经酸性成纤维细胞生长因子治疗后,大鼠小肠组织p38MAPK蛋白及成纤维细胞生长因子受体2蛋白和mRNA的表达进一步增强,小肠黏膜损伤程度减轻。说明酸性成纤维细胞生长因子可通过上调成纤维细胞生长因子受体2和p38MAPK的表达促进肠缺血-再灌注损伤的修复。     

FGF-2 potentiates Ca(2+)-dependent inactivation of NMDA receptor currents in hippocampal neurons

Peptide growth factors such as the neurotrophins and fibroblast growth factors have potent effects on synaptic transmission, development, and cell survival. We report that chronic (hours) treatment with basic fibroblast growth factor (FGF-2) potentiates Ca(2+)-dependent N-methyl-D-aspartate (NMDA) receptor inactivation in cultured hippocampal neurons. This effect is specific for the NMDA-subtype of ionotropic glutamate receptor and FGF-2. The potentiated inactivation requires ongoing protein synthesis during growth factor treatment and the activity of protein phosphatase 2B (PP2B or calcineurin) during agonist application. These results suggest a mechanism by which FGF-2 receptor signaling may regulate neuronal survival and synaptic plasticity.     

Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair through the Akt1 pathway

BackgroundFibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair. Fibroblast growth factor-2 acts through betaglycan which is known to bind both transforming growth factor-β and fibroblast growth factor-2 at different locations on the molecule. When fibroblast growth factor-2 binds to betaglycan, transforming growth factor-β binding to betaglycan is reduced, allowing for more transforming growth factor-β to be available to activate pSmad2/3 which then promotes repair. This study investigates another pathway through which fibroblast growth factor-2 regulates valve interstitial cell repair.MethodsWe used an in vitro model of cell culture disruption. Confluent valve interstitial cell monolayers were disrupted, creating an experimental wound in the confluent monolayer, and incubated in treatments of exogenous fibroblast growth factor-2, anti-fibroblast growth factor receptor antibody, active Akt1, and Akt inhibitor. Valve interstitial cell monolayers were immunohistochemically stained and quantified for nuclear pSmad2/3 at the wound edge. The extent of closure was measured up to 96 h after disruption.ResultsAnti-fibroblast growth factor receptor antibody significantly increased both nuclear pSmad2/3 staining at the wound edge and wound closure compared to nontreated control. This increase was less than that seen when valve interstitial cells were treated with fibroblast growth factor-2 and combined treatments of fibroblast growth factor-2 and anti-fibroblast growth factor receptor antibody did not further increase nuclear pSmad2/3 staining compared to fibroblast growth factor-2 alone. This suggested that the regulation of wound closure by fibroblast growth factor-2 also involved pathways other than transforming growth factor-β/Smad signaling. Treatment with Akt1 significantly increased wound closure, while Akt inhibitor reduced closure as compared to nontreated valve interstitial cells. Fibroblast growth factor-2 and fibroblast growth factor-2 neutralizing antibody up-regulated and down-regulated phosphorylated Akt1 expression in valve interstitial cells, respectively.ConclusionFibroblast growth factor-2 promotes valve interstitial cell repair in two ways: the fibroblast growth factor-2/fibroblast growth factor-2 receptor interaction through the activation of Akt1 independent of the transforming growth factor-β/Smad2/3 signaling pathway and the previously described transforming growth factor-β/Smad signaling.