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Journal ArticleDOI

Fibroblast growth factors, their receptors and signaling.

01 Sep 2000-Endocrine-related Cancer (Bioscientifica Ltd)-Vol. 7, Iss: 3, pp 165-197
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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Citations
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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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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Book ChapterDOI
TL;DR: This chapter focuses on isolation and characterization of acidic and basic fibroblast growth factor, which has been shown to bind to specific and high affinity cell surface receptor, and to trigger the pleiotypic cell response.
Abstract: Publisher Summary This chapter focuses on isolation and characterization of acidic and basic fibroblast growth factor. Basic fibroblast growth factor (FGF) is originally isolated from bovine brain and pituitary. It is also present in a wide range of other organs. It has been shown to be mitogenic for endothelial cells and a wide variety of mesoderm and neuroectoderm-derived cells. In addition, it is also a differentiation factor preventing the dedifferentiation of cultured vascular and corneal endothelial cells, chondrocytes, and myoblast, and inducing differentiation in nerve cells (PC-12) and conversion of fibroblasts into adipocytes. At the cellular level, FGF has been shown to bind to specific and high affinity cell surface receptor, and to trigger the pleiotypic cell response, as well as increase expression of mRNA transcripts of the cellular oncogenes c-myc and c-fos. In vivo basic FGF is an angiogenic factor.

128 citations


"Fibroblast growth factors, their re..." refers background in this paper

  • ...That such a large functional reservoir of FGFs exists is clear from the observation that the EC50 of FGF-2 for its receptor is approximately 1 ng/ml, while the tissue concentration of FGF-2 has been found to be between 10 and 500 ng/ml (Gospodarowicz 1987)....

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Journal ArticleDOI
TL;DR: Recombinant human FGF-10 showed mitogenic activity for fetal rat keratinizing epidermal cells, but essentially no activity for NIH/3T3 cells, fibroblasts, and the cDNA encoding a novel member of the human fibroblast growth factor (FGF) family was isolated from the lung.

125 citations


"Fibroblast growth factors, their re..." refers background in this paper

  • ...FGF-10 is a 208 amino acid glycoprotein with a signal sequence (Emoto et al. 1997)....

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  • ...FGF-10 has a high protein sequence similarity to FGF-7 and they are both mitogenic for keratinocytes (Emoto et al. 1997)....

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Journal ArticleDOI
TL;DR: Examination of platelet‐derived growth factor and PDGF receptors was examined in cultured human pancreatic cancer cells, in the normal human pancreas and in pancreatic adenocarcinomas, and by immunohistochemistry, PDGF and bothPDGF receptors were present in the cancer cells.
Abstract: Expression of platelet-derived growth factor (PDGF) and PDGF receptors was examined in cultured human pancreatic cancer cells, in the normal human pancreas and in pancreatic adenocarcinomas. mRNA transcripts encoding PDGF A and B chains, and PDGF receptor beta (PDGFR beta) were present in PANC-I and HPAF human pancreatic cancer cells. Transforming growth factor beta I (TGF-beta I), but not PDGF-AA or -BB, enhanced PDGF A and B chain mRNA levels in both cell lines. In the normal human pancreas PDGF A chain mRNA levels were relatively abundant, whereas PDGF B chain mRNA levels were not detected and PDGF receptor alpha (PDGFR alpha) and beta mRNA transcripts were present at low levels. PDGF immunoreactivity was present in islet cells, and PDGFR alpha was present in acinar cells, whereas PDGFR beta was present in acinar cells and in the connective tissue. In the pancreatic cancers, PDGF A chain mRNA transcripts were also abundant, and 6 of 13 samples exhibited the PDGF B chain mRNA transcript. In addition, there was a 7-fold increase in the levels of PDGFR alpha and PDGFR beta in the cancer samples by comparison with the normal pancreas. By immunohistochemistry, PDGF and both PDGF receptors were present in the cancer cells, and PDGFR beta was abundant in fibroblasts and endothelial cells within the connective tissue.

124 citations

Journal ArticleDOI
TL;DR: It is shown that the interaction of heparin with FGF ligands is not affected by divalent cations, and a model is proposed where doval cations and heparan sulfate cooperate to maintain FGFR in a conformation that restricts trans-phosphorylation between intracellular kinase domains.

122 citations

Journal ArticleDOI
TL;DR: Expression of the secreted BP appears to be a mechanism through which immobilized FGF can be activated to support tumor growth and angiogenesis.

122 citations


Additional excerpts

  • ...in nude mice (Czubayko et al. 1994)....

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