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
References
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TL;DR: Chromosome 18-specific DNA probes for the areas flanking the breakpoints also detected RNA transcripts 6 kilobases in length in various cell types, and the gene coding for these transcript seems to be interrupted in most cases of follicular lymphomas carrying the t(14;18) chromosomal translocation.
Abstract: Recombinant DNA probes were cloned for the areas flanking the breakpoint on chromosome 18 in cells from a patient with acute lymphocytic leukemia of the B-cell type; cells of this line carry the t(14;18) chromosomal translocation. Two of the probes detected DNA rearrangements in approximately 60 percent of the cases of follicular lymphoma screened. In follicular lymphoma, most of the breakpoints in band q21 of chromosome 18 were clustered within a short stretch of DNA, approximately 2.1 kilobases in length. Chromosome 18-specific DNA probes for the areas flanking the breakpoints also detected RNA transcripts 6 kilobases in length in various cell types. The gene coding for these transcript (the bcl-2 gene) seems to be interrupted in most cases of follicular lymphomas carrying the t(14;18) chromosomal translocation.
1,854 citations
TL;DR: These findings define a single cell-surface receptor that regulates both matrix degradation and motility, thereby facilitating directed cellular invasion.
1,544 citations
TL;DR: Prevention of binding between cell surface heparan sulfate and bFGF substantially reduces binding of fibroblast growth factor to its cell-surface receptors, blocks the ability of bF GF to support the growth of Swiss 3T3 fibroblasts, and induces terminal differentiation of MM14 skeletal muscle cells, which is normally repressed by fibro Blast growth factor.
Abstract: Basic fibroblast growth factor (bFGF) binds to heparan sulfate proteoglycans at the cell surface and to receptors with tyrosine kinase activity. Prevention of binding between cell surface heparan sulfate and bFGF (i) substantially reduces binding of fibroblast growth factor to its cell-surface receptors, (ii) blocks the ability of bFGF to support the growth of Swiss 3T3 fibroblasts, and (iii) induces terminal differentiation of MM14 skeletal muscle cells, which is normally repressed by fibroblast growth factor. These results indicate that cell surface heparan sulfate is directly involved in bFGF cell signaling.
1,516 citations
TL;DR: Understanding the mechanisms by which pericellular proteinases are regulated and activated, the nature of their molecular targets, and how adhesion and proteolysis are integrated will provide exciting avenues for investigation over the next few years.
1,318 citations
TL;DR: The characterization of structural and functional diversity within the F GF receptor shows the differences in the mechanisms of action among members of the FGF family.
Abstract: Publisher Summary The fibroblast growth factors (FGFs) constitute a family of closely related polypeptide mitogens There are seven members of this family, identified on the basis of amino acid sequence homologies The FGF family has distinguished itself from other growth factor families by virtue of the pleiotropic actions of its members This chapter discusses the structural and functional diversity in the FGF receptor multigene family The effects of FGFs are known to be mediated by high-affinity receptor tyrosine kinases The structurally diverse receptor molecules are also functionally different The characterization of structural and functional diversity within the FGF receptor shows the differences in the mechanisms of action among members of the FGF family The first members of the FGF family to be purified and characterized were acidic FGF (aFGF) and basic FGF (bFGF), which are purified on the basis of their mitogenicity toward fibroblasts by using bovine pituitary Functional differences among the different receptor forms are observed in the chapter at two levels The long-range goal of designing the effective agonist and antagonists of FGF action has considerable therapeutic value
1,267 citations
"Fibroblast growth factors, their re..." refers background in this paper
...There are now four known FGF receptors, FGFR-1 through FGFR-4, which hare between 55% and 72% homology at the protein level (Johnson & Williams 1993) (see Fig....
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...Gene is activated by E2A-Pbx1 FGFs 16–19 FGF-17; FGFR-1, IIIc; FGFR-2, IIIc¶ All have signal sequence FGF-20 XFGF-20 Unknown?...
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...Interestingly, this structure is Downloaded from Bioscientifica.com at 12/27/2018 11:42:59AM via free access Table 1 Characteristics of the members of the FGF family Name Synonym(s) Signaling through high-affinity Comments* receptors† FGF-1 Acidic FGF, aFGF FGFR-1, IIIb & IIIc; FGFR-2, IIIb & 1 mRNA form, no signal sequence, nuclear IIIc; FGFR-3, IIIb & IIIc; FGFR-4 localization motif FGF-2 Basic FGF, bFGF FGFR-1, IIIb & IIIc; FGFR-2, IIIc; 4 protein isoforms through the use of alternate FGFR-3, IIIc; FGFR-4 start codons, no signal sequence, some isoforms have nuclear localization motifs FGF-3 Int-2 FGFR-1, IIIb; FGFR-2, IIIb Site of MMTV integration in mouse genome, signal sequence, nuclear localization motif FGF-4 kFGF, kaposi FGF, FGFR-1, IIIc; FGFR-2, IIIc; FGFR-3, Identified by screening stomach tumors and hst-1 IIIc; FGFR-4 Kaposi’s sarcoma, signal sequence FGF-5 FGFR-1, IIIc; FGFR-2, IIIc Signal sequence FGF-6 hst-2 FGFR-1, IIIc; FGFR-2, IIIc, FGFR-4 Signal sequence FGF-7 KGF FGFR-2, IIIb Specific for epithelial cells, signal sequence FGF-8 AIGF FGFR-1,‡ FGFR-2, IIIc; FGFR-3, 7 isoforms, all with signal sequences IIIc, FGFR-4 FGF-9 GAF FGFR-2, IIIc; FGFR-3, IIIb & IIIc, No signal sequence, not angiogenic FGFR-4 FGF-10 KGF-2 FGFR-1, IIIb; FGFR-2, IIIb§ Signal sequence, similar in structure and function to FGF-7 FGFs 11–14 FGFs Unknown?...
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...SNT-1/FRS2 is localized to the inner leaflet of the cell membrane by myristylation and interacts with FGFR-1 at amino acids 407-433 of the juxtamembrane region (Xuet al. 1998)....
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...It has also been demonstrated that cell surface HLGAGs not only facilitate binding to FGFR-1, but also to FGFR-2 (Mansukhaniet al. 1992), and that this binding facilitates www.endocrinology.org 175 FGF signaling, triggering mitogenesis and angiogenesis (Rapraegeret al. 1991, Aviezeret al. 1994)....
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