成纤维细胞生长因子的双受体系统

成纤维细胞生长因子(FGFs)对于细胞代谢的刺激作用是通过双受体系统（dual-receptor system）介导的.该系统包括一个酪氨酸激酶受体家族(FGFRs)及肝素硫酸蛋白多糖(HSPG).目前已知有4种FGFRs基因,其转录过程表现出剪切多样性.FGFs与FGFRs的结合表现出交叉特异性.HSPG可促进FGFs与FGFRs的结合和受体二聚体的形成,并增强FGFs对细胞调控的精度.FGFRs通过激活不同下游信号分子影响细胞有丝分裂、神经细胞轴突生长、胚胎发育等.     

FGF23/α-Klotho信号传导的分子机制

成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)是内分泌型FGFs家族中的重要一员,是一种重要的骨源性调磷激素。FGF23主要通过结合成纤维细胞生长因子受体(fibroblast growth factor receptor,FGFRs)/α-Klotho的复合物来调控肾脏中磷和维生素D的代谢。FGF23信号通路的异常与多种代谢性疾病尤其是慢性肾病(chronic kidney disease,CKD)有非常密切的关系。FGF23水平的不断上升是导致CKD患者疾病进程加快、诱发并发症甚至最终死亡的主要因素。通过对最近发表的FGF23-FGFR1c-α-Klotho三元复合物蛋白结构的分析,更好地阐明FGF23蛋白信号传导的分子机制,为相关疾病的治疗或药物开发提供新的策略。     

角质细胞生长因子的研究进展

角质细胞生长因子（KGF）是成纤维细胞生长因子（FGFs）家族的成员,即FGF－7,最初是从人胚胎肺成纤维细胞的培养上清中分离纯化获得的。成熟KGF为一163个氨基酸残基的单链多肽,分子量为26－28KD。KGF由各种来源的间质细胞分泌,受体分布于上皮细胞,其生物学活性是特异性地促进上皮细胞的增殖、迁移和分化。FGF的表达受激素和一些细胞因子的调控。有关研究表明,KGF对肺泡Ⅱ型细胞的增殖以及皮肤、胃肠道粘膜和角膜损伤的修复具有十分重要的作用。     

FGF10:胚胎器官发育中重要的多功能信号分子

从诱导脊椎动物早期胚胎的中胚层到器官和组织的形成,成纤维细胞生长因子家族(FGFs)在其各个阶段起着重要的作用。FGFs在各种器官形成中担负上皮间质相互作用的重要调控因子,特别是FGF10,无论在外胚层上皮还是在内皮层上皮都是重要的间质调控因子。如果离开该因子,胚胎组织器官发生将无法完成。就FGF10调控四肢、支气管-肺脏、胰腺、脑垂体、皮肤、牙齿、下颌下腺和白色脂肪等组织器官形态发生的最新研究进展进行综述。     

成纤维细胞生长因子的生理病理作用及应用进展

成纤维细胞生长因子(fibroblast growth factors,FGFs)以旁分泌或内分泌的方式参与多种生理活动的调节,维护成体组织的正常结构、功能并参与代谢调控。FGFs通过结合配体硫酸乙酰肝素或klotho使成纤维细胞生长因子受体二聚化而发挥生物学作用。过去的十年中,FGFs结构和分子机制的研究成果改变了人们对FGF信号在人类健康和疾病发生、发展中的认识,为以FGF及其受体为靶点的药物开发带来新的突破。文章综述了FGF的生理、病理作用及最新应用研究进展。     

成纤维细胞生长因子9(FGF9)的研究进展

成纤维细胞生长因子9(fibroblast growth factor 9,FGF9)是成纤维细胞生长因子家族(FGFs)的成员之一。广泛分布于人体各种组织中,它参与骨骼发育、血管形成、胚胎发育、损伤修复、细胞凋亡、神经再生、肿瘤生长等多种生理和病理的过程,可有效促进有丝分裂和细胞生长。研究发现,FGF9不仅在骨骼发育和生长期对软骨形成和成骨生成起着重要的作用,而且对卵巢癌的发生、神经再生、性腺分化等方面也有重要的影响,对FGF9作为一个有用治疗靶点发挥作用的功能和机制仍有待进一步的发现及研究。现针对FGF9的特点,综述了其在表达及适应征机制方面的研究进展,为FGF9进一步的研究及合理开发利用提供参考。     

运动调控FGF21在改善肥胖相关代谢性疾病中的作用

肥胖是糖尿病、脂肪肝、心血管疾病等慢性代谢性疾病发生发展的重要风险因素。运动可以改善肥胖,对相关代谢性疾病的预防与康复具有积极作用。成纤维细胞生长因子21 (fibroblast growth factor 21,FGF21)是一种对机体能量稳态、糖脂代谢有积极调控作用的内分泌因子,是代谢性疾病预防和治疗的有效靶点之一。FGF21抵抗是机体对FGF21反应性减弱的现象,表现为靶组织生物学效应降低,机体FGF21代偿性合成增加。这可能是由FGF21受体(fibroblast growth factor receptors,FGFRs)和β-klotho蛋白(β-klotho,KLB)表达减少或敏感性降低所致。肥胖患者常出现FGF21抵抗,改善FGF21抵抗是治疗肥胖及相关代谢性疾病的新思路。运动不仅可以增加部分组织FGF21表达量,还可以刺激FGFRs与KLB的表达来敏化FGF21的作用,改善FGF21抵抗。     

FGFR2IIIc胞外段的原核表达及其对前列腺癌细胞增殖的抑制作用

将FGFR2IIIc胞外段基因转入pET3c载体,并通过大肠杆菌使其以包涵体形式表达。经透析法复性和肝素亲和层析纯化,得到纯度95%以上的目的蛋白。通过免疫共沉淀方法证实复性后的FGFR2IIIc胞外段与FGF2之间可特异性结合,并对前列腺癌DU145细胞的增殖具有明显的抑制作用（MTT法）。免疫印迹结果显示FGFR2IIIc胞外段可显著下调DU145细胞膜上FGFRs的磷酸化水平,提示由于有效阻断FGFs的细胞内信号通路,从而导致FGFR2IIIc胞外段对肿瘤细胞增殖的抑制。     

FGFR2Ⅲc胞外段的原核表达及其对前列腺癌细胞增殖的抑制作用

将FGFR2Ⅲc胞外段基因转入pEt3c载体,并通过大肠杆菌使其以包涵体形式表达.经透析法复性和肝素亲和层析纯化,得到纯度95%以上的目的蛋白.通过免疫共沉淀方法证实复性后的FGFR2Ⅲc胞外段与FGF2之间可特异性结合,并对前列腺癌DU145细胞的增殖具有明显的抑制作用(MTT法).免疫印迹结果显示FGFR2Ⅲc胞外段可显著下调DU145细胞膜上FGFRs的磷酸化水平,提示由于有效阻断FGFs的细胞内信号通路,从而导致FGFR2Ⅲc胞外段对肿瘤细胞增殖的抑制.     

成纤维细胞生长因子受体-癌症治疗新靶点

成纤维细胞生长因子(FGFs)通过作用于其受体(成纤维细胞生长因子受体,FGFRs)在许多生理过程中发挥重要作用,如胚胎形成、创伤修复、血管生成等。近年来,越来越多的证据表明FGFRs是某些癌症的驱动基因,并且以"细胞自治"的方式维持肿瘤细胞的恶性特征,通过诱导促有丝分裂和生存信号、促进肿瘤细胞侵袭转移、促进上皮间质转化、促进血管生成及参与肿瘤复发耐药作用作为癌基因参与肿瘤发生发展进程的多重步骤,但也有研究证实FGFR信号在某些肿瘤类型中具有抑制肿瘤的功能。这些研究结果使得FGFRs成为越来越具有吸引力的癌症治疗新靶点。本文阐述了FGFRs信号通路在多种肿瘤中的作用,并且对处于研发或试验阶段的抗FGFRs药物(包括小分子酪氨酸激酶抑制剂和单克隆抗体)进行了概括。     

Role of FGFs/FGFRs in skeletal development and bone regeneration

Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling‐related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing. J. Cell. Physiol. 227: 3731–3743, 2012. © 2012 Wiley Periodicals, Inc.     

Fibroblast growth factors and their receptors in the central nervous system

Fibroblast growth factors (FGFs) and their receptors constitute an elaborate signaling system that participates in many developmental and repair processes of virtually all mammalian tissues. Among the 23 FGF members, ten have been identified in the brain. Four FGF receptors (FGFRs), receptor tyrosine kinases, are known so far. Ligand binding of these receptors greatly depends on the presence of heparan sulfate proteoglycans, which act as low affinity FGFRs. Ligand binding specificity of FGFRs depends on the third extracellular Ig-like domain, which is subject to alternative splicing. Activation of FGFRs triggers several intracellular signaling cascades. These include phosphorylation of src and PLC leading finally to activation of PKC, as well as activation of Crk and Shc. SNT/FRS2 serves as an alternative link of FGFRs to the activation of PKC and, in addition, activates the Ras signaling cascade. In the CNS, FGFs are widely expressed; FGF-2 is predominantly synthesized by astrocytes, whereas other FGF family members, e.g., FGF-5, FGF-8, and FGF-9, are primarily synthesized by neurons. During CNS development FGFs play important roles in neurogenesis, axon growth, and differentiation. In addition, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis depends greatly on FGF-2. Finally, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory.     

Role of fibroblast growth factors in elicitation of cell responses

Fibroblast growth factors (FGFs) are signalling peptides that control important cell processes such as proliferation, differentiation, migration, adhesion and survival. Through binding to different types of receptor on the cell surface, these peptides can have different effects on a target cell, the effect achieved depending on many features. Thus, each of the known FGFs elicits specific biological responses. FGF receptors (FGFR 1–5) initiate diverse intracellular pathways, which in turn lead to a variety of results. FGFs also bind the range of FGFRs with a series of affinities and each type of cells expresses FGFRs in different qualitative and quantitative patterns, which also affect responses. To summarize, cell response to binding of an FGF ligand depends on type of FGF, FGF receptor and target cell, all interacting in concert. This review aims to examine properties of the FGF family and its members receptors. It also aims to summarize features of intracellular signalling and highlight differential effects of the various FGFs in different circumstances.     

Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family

In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1-4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1-9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10-23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity.     

Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4

Fibroblast growth factors (FGFs) are heparin-binding polypeptides that affect the growth, differentiation, and migration of many cell types. FGFs signal by binding and activating cell surface FGF receptors (FGFRs) with intracellular tyrosine kinase domains. The signaling involves ligand-induced receptor dimerization and autophosphorylation, followed by downstream transfer of the signal. The sulfated glycosaminoglycans heparin and heparan sulfate bind both FGFs and FGFRs and enhance FGF signaling by mediating complex formation between the growth factor and receptor components. Whereas the heparin/heparan sulfate structures involved in FGF binding have been studied in some detail, little information has been available on saccharide structures mediating binding to FGFRs. We have performed structural characterization of heparin/heparan sulfate oligosaccharides with affinity toward FGFR4. The binding of heparin oligosaccharides to FGFR4 increased with increasing fragment length, the minimal binding domains being contained within eight monosaccharide units. The FGFR4-binding saccharide domains contained both 2-O-sulfated iduronic acid and 6-O-sulfated N-sulfoglucosamine residues, as shown by experiments with selectively desulfated heparin, compositional disaccharide analysis, and a novel exoenzyme-based sequence analysis of heparan sulfate oligosaccharides. Structurally distinct heparan sulfate octasaccharides differed in binding to FGFR4. Sequence analysis suggested that the affinity of the interaction depended on the number of 6-O-sulfate groups but not on their precise location.     

Small molecule inhibition of fibroblast growth factor receptors in cancer

Fibroblast growth factors (FGFs) signal through FGF receptors (FGFRs), which are a sub-family of the superfamily of receptor tyrosine kinases, to regulate human development and metabolism. Uncontrolled FGF signaling is responsible for diverse array of developmental disorders, most notably skeletal syndromes due to FGFR gain-of-function mutations. Studies in the last few years have provided significant evidence for the importance of FGF signaling in the pathogenesis of diverse cancers, including endometrial and bladder cancers. FGFs are both potent mitogenic and angiogenic factors and can contribute to carcinogenesis by stimulating cell proliferation and tumor angiogenesis. Gene knockout and pharmacological inhibition of FGFRs in in vivo and in vitro models validate FGFRs as a target for cancer treatment. Considerable efforts are being expended to develop specific, small-molecule inhibitors for treating FGFR-driven cancers. Recent reviews on the FGF/FGFR system have focused primarily on signaling, pathophysiology, and functions in cancer. In this article, we review the key roles of FGFR in cancer, provide an update on the status of clinical trials with small-molecule FGFR inhibitors, and discuss how the current structural data on FGFR kinases guide the design and characterization of new FGFR inhibitors.     

Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes

We have developed an in vivo mouse model, the green fluorescent protein (GFP)/carbon tetrachloride (CCl₄) model, and have previously reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes via hepatoblast intermediates. Here, we have investigated the growth factors that are closely related to the differentiation of transplanted BMCs into hepatocytes, and the way that a specific growth factor affects the differentiation process in the GFP/CCl₄ model. We performed immunohistochemical analysis to identify an important growth factor in our model, viz., fibroblast growth factor (FGF). In liver samples, the expression of FGF1 and FGF2 and of FGF receptors (FGFRs; FGFR1, FGFR2) was significantly elevated with time after bone marrow transplantation (BMT) compared with other factors, and co-expression of GFP and FGFs or FGFRs could be detected. We then analyzed the effect and molecular mechanism of FGF signaling on the enhancement of BMC differentiation into hepatocytes by immunohistochemistry, immunoblotting, and microarray analysis. Treatment with recombinant FGF (rFGF), especially rFGF2, elevated the repopulation rate of GFP-positive cells in the liver and significantly increased the expression of both Liv2 (hepatoblast marker) and albumin (hepatocyte marker). Administration of rFGF2 at BMT also raised serum albumin levels and improved the survival rate. Transplantation of BMCs with rFGF2 specifically activated tumor necrosis factor-alpha (TNF-α) signaling. Thus, FGF2 facilitates the differentiation of transplanted BMCs into albumin-producing hepatocytes via Liv2-positive hepatoblast intermediates through the activation of TNF-α signaling. Administration of FGF2 in combination with BMT improves the liver function and prognosis of mice with CCl₄-induced liver damage. This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (nos. 13470121, 13770262, 15790348, 16390211, and 16590597) and for translational research from the Ministry of Health, Labor and Welfare (H-trans-5).     

The roles of the FGF signal in zebrafish embryos analyzed using constitutive activation and dominant-negative suppression of different FGF receptors

The roles of the FGF family growth factors and their receptors (FGFRs) in zebrafish embryos were examined using variously modified versions of the four FGFR genes (fgfr1–4). Constitutively active forms of all of the examined FGFRs (ca-FGFRs) caused dorsalization, brain caudalization, and secondary axis formation, indicating that the main FGF signal transduction downstream of the receptor is highly similar among FGFRs. All of the membrane-bound type of dominant-negative FGFRs (mdn-FGFRs) derived from the four fgfr genes, which interfere with endogenous FGFRs, produced posterior truncation, as previously reported in both Xenopus and zebrafish. mdn-FGFR3c had the strongest effects on embryos, progressively disrupting the posterior structure as the dose increased. At the highest dose, only the forebrain was formed. At lower doses, mdn-FGFR3c mainly suppressed the paraxial mesoderm. The co-injection of mRNA for different mdn-FGFRs and FGFs resulted in diverse suppression spectra of the respective FGFRs against FGFs. Only mdn-FGFR3c severely suppressed all of the FGFs examined. We also examined the effects of the secretory type of dominant-negative FGFRs (sdn-FGFRs), which are released from cells and trap FGF ligands. Only sdn-FGFR3c resulted in the characteristic effect of selectively disrupting the isthmic development, as well as the tailbud. The co-injection of the mRNA for sdn-FGFRs and FGFs suggested that sdn-FGFR3c inhibits FGFs of the FGF8 subfamily, which is consistent with its specific effects on development. We discuss the implications of our findings obtained in the present study.     

FGF2 promotes skeletogenic differentiation of cranial neural crest cells

The cranial neural crest gives rise to most of the skeletal tissues of the skull. Matrix-mediated tissue interactions have been implicated in the skeletogenic differentiation of crest cells, but little is known of the role that growth factors might play in this process. The discovery that mutations in fibroblast growth factor receptors (FGFRs) cause the major craniosynostosis syndromes implicates FGF-mediated signalling in the skeletogenic differentiation of the cranial neural crest. We now show that, in vitro, mesencephalic neural crest cells respond to exogenous FGF2 in a dose-dependent manner, with 0.1 and 1 ng/ml causing enhanced proliferation, and 10 ng/ml inducing cartilage differentiation. In longer-term cultures, both endochondral and membrane bone are formed. FGFR1, FGFR2 and FGFR3 are all detectable by immunohistochemistry in the mesencephalic region, with particularly intense expression at the apices of the neural folds from which the neural crest arises. FGFRs are also expressed by subpopulations of neural crest cells in culture. Collectively, these findings suggest that FGFs are involved in the skeletogenic differentiation of the cranial neural crest.