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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TL;DR: A review of the specific roles of these growth factors and cytokines during wound healing can be found in this article, where patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF.
Abstract: Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor necrosis factor-alpha family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.
2,617 citations
TL;DR: A subset of the FGF family, expressed in adult tissue, is important for neuronal signal transduction in the central and peripheral nervous systems.
Abstract: Fibroblast growth factors (FGFs) make up a large family of polypeptide growth factors that are found in organisms ranging from nematodes to humans. In vertebrates, the 22 members of the FGF family range in molecular mass from 17 to 34 kDa and share 13-71% amino acid identity. Between vertebrate species, FGFs are highly conserved in both gene structure and amino-acid sequence. FGFs have a high affinity for heparan sulfate proteoglycans and require heparan sulfate to activate one of four cell-surface FGF receptors. During embryonic development, FGFs have diverse roles in regulating cell proliferation, migration and differentiation. In the adult organism, FGFs are homeostatic factors and function in tissue repair and response to injury. When inappropriately expressed, some FGFs can contribute to the pathogenesis of cancer. A subset of the FGF family, expressed in adult tissue, is important for neuronal signal transduction in the central and peripheral nervous systems.
2,228 citations
TL;DR: It is concluded that FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.
Abstract: Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.
1,921 citations
TL;DR: Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning.
Abstract: The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs) Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer © 2015 Wiley Periodicals, Inc
1,445 citations
TL;DR: 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.
1,052 citations
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TL;DR: The complete amino acids sequence of human ECGF was deduced from the nucleic acid sequence of these clones; it encompasses all the well-characterized acidic endothelial cell polypeptide mitogens described by several laboratories.
Abstract: Several of the endothelial cell polypeptide mitogens that have been described probably play a role in blood vessel homeostasis. Two overlapping complementary DNA clones encoding human endothelial cell growth factor (ECGF) were isolated from a human brain stem complementary DNA library. Southern blot analysis suggested that there is a single copy of the ECGF gene and that it maps to human chromosome 5 at bands 5q31.3 to 33.2 A 4.8-kilobase messenger RNA was present in human brain stem messenger RNA. The complete amino acid sequence of human ECGF was deduced from the nucleic acid sequence of these clones; it encompasses all the well-characterized acidic endothelial cell polypeptide mitogens described by several laboratories. The ECGF-encoding open reading frame is flanked by translation stop codons and provides no signal peptide or internal hydrophobic domain for the secretion of ECGF. This property is shared by human interleukin-1, which is approximately 30 percent homologous to ECGF.
640 citations
"Fibroblast growth factors, their re..." refers background in this paper
...The FGF-5 protein is 267 amino acids long and has 40% and 50% homology in the core region to FGF-1 and -2 respectively (Zhanet al. 1988, Bateset al. 1991, Goldfarbet al. 1991)....
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...Kiefer et al. (1993) have proposed that FGF-3 is slowly secreted because of the unique character of its amino-terminal glycosylation site, which may sequester FGF-3 in the Golgi apparatus....
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...Consequently, the current understanding of the ability of FGFs to activate their receptors is that they induce receptor dimerization, and that this dimerization is facilitated by HLGAGs....
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...Although the PLCγ pathway is not directly involved in cell motility (Langrenet al. 1998), it may be involved in some other form of cytoskeletal alteration as the actin-binding protein profillin participates in PLCγ signaling (Goldschmidt-Clermontet al. 1991)....
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...Consequently, the improvement that Kiefer and coworkers observed may be due to altered competition between secretion and nuclear localization rather than the glycosylation effect resulting in Golgi retention....
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TL;DR: The putative bFGF receptor encoded by this complementary DNA is a transmembrane protein that contains three extracellular immunoglobulin-like domains, an unusual acidic region, and an intracellular tyrosine kinase domain that is different from that of any growth factor receptor described.
Abstract: Basic fibroblast growth factor (bFGF) participates in many processes including early developmental events, angiogenesis, wound healing, and maintenance of neuronal cell viability. A 130-kilodalton protein was isolated on the basis of its ability to specifically bind to bFGF. A complementary DNA clone was isolated with an oligonucleotide probe corresponding to determined amino acid sequences of tryptic peptide fragments of the purified protein. The putative bFGF receptor encoded by this complementary DNA is a transmembrane protein that contains three extracellular immunoglobulin-like domains, an unusual acidic region, and an intracellular tyrosine kinase domain. These domains are arranged in a pattern that is different from that of any growth factor receptor described.
627 citations
"Fibroblast growth factors, their re..." refers background in this paper
...(1995) saw no direct interaction and instead proposed that, as the Tyr766 to Phe766 mutant had high levels of phosphorylated Src, the PLCγ pathway inhibits Src activity....
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TL;DR: The complete cDNA cloning of two human genes previously designated flg and bek is reported, indicating that bek and flg bind either aFGF or bFGF with dissociation constants of (2‐15) x 10(‐11) M.
Abstract: The fibroblast growth factor (FGF) family consists of at least seven closely related polypeptide mitogens which exert their activities by binding and activation of specific cell surface receptors. Unanswered questions have been whether there are multiple FGF receptors and what factors determine binding specificity and biological response. We report the complete cDNA cloning of two human genes previously designated flg and bek. These genes encode two similar but distinct cell surface receptors comprised of an extracellular domain with three immunoglobulin-like regions, a single transmembrane domain, and a cytoplasmic portion containing a tyrosine kinase domain with a typical kinase insert. The expression of these two cDNAs in transfected NIH 3T3 cells led to the biosynthesis of proteins of 150 kd and 135 kd for flg and bek, respectively. Direct binding experiments with radiolabeled acidic FGF (aFGF) or basic FGF (bFGF), inhibition of binding with native growth factors, and Scatchard analysis of the binding data indicated that bek and flg bind either aFGF or bFGF with dissociation constants of (2-15) x 10(-11) M. The high affinity binding of two distinct growth factors to each of two different receptors represents a unique double redundancy without precedence among polypeptide growth factor-receptor interactions.
613 citations
"Fibroblast growth factors, their re..." refers background in this paper
...Cloning of the human FGF receptor (FGFR) genes identified the first two,fgfr-1 and fgfr-2, asflg and bek (Dionne et al. 1990), both of which were previously identified tyrosine kinase proteins (Kornbluth et al. 1988, Rutaet al. 1989)....
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...Cloning of the human FGF receptor (FGFR) genes identified the first two, fgfr-1 and fgfr-2, asflg and bek (Dionne et al. 1990), both of which were previously identified tyrosine kinase proteins (Kornbluth et al....
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TL;DR: Results indicate that FGF2, although not essential for embryonic development, plays a specific role in cortical neurogenesis and skin wound healing in mice, which, in spite of the apparent redundancy of FGF signaling, cannot be carried out by other FGF family members.
Abstract: Basic fibroblast growth factor (FGF2) is a wide-spectrum mitogenic, angiogenic, and neurotrophic factor that is expressed at low levels in many tissues and cell types and reaches high concentrations in brain and pituitary. FGF2 has been implicated in a multitude of physiological and pathological processes, including limb development, angiogenesis, wound healing, and tumor growth, but its physiological role is still unclear. To determine the function of FGF2 in vivo, we have generated FGF2 knockout mice, lacking all three FGF2 isoforms, by homologous recombination in embryonic stem cells. FGF2−/− mice are viable, fertile and phenotypically indistinguishable from FGF2+/+ littermates by gross examination. However, abnormalities in the cytoarchitecture of the neocortex, most pronounced in the frontal motor-sensory area, can be detected by histological and immunohistochemical methods. A significant reduction in neuronal density is observed in most layers of the motor cortex in the FGF2−/− mice, with layer V being the most affected. Cell density is normal in other regions of the brain such as the striatum and the hippocampus. In addition, the healing of excisional skin wounds is delayed in mice lacking FGF2. These results indicate that FGF2, although not essential for embryonic development, plays a specific role in cortical neurogenesis and skin wound healing in mice, which, in spite of the apparent redundancy of FGF signaling, cannot be carried out by other FGF family members.
601 citations
TL;DR: Evidence is provided that FGF8 serves as an endogenous inducer of chick limb formation and that its expression in the intermediate mesoderm at the appropriate time and place to trigger forelimb development is directly linked to the mechanism of embryonic kidney differentiation.
597 citations