Fibroblast growth factors, their receptors and signaling.

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 they can bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs may act directly on target cells, or they can be released through digestion of the ECM or the activity of 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, ultimately resulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most play important roles in embryonic development and wound healing. 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.

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Regulation of Hepatic Stellate Cells and Fibrogenesis by Fibroblast Growth Factors

BioMed Research International ◽

10.1155/2016/8323747 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 27

Author(s):

Justin D. Schumacher ◽

Grace L. Guo

Keyword(s):

Wound Healing ◽

Growth Factors ◽

Hepatic Stellate Cells ◽

Therapeutic Strategy ◽

Fibroblast Growth Factors ◽

Stellate Cells ◽

Fibroblast Growth ◽

Fgf Signaling ◽

Paracrine Regulation ◽

Hepatocyte Regeneration

Fibroblast growth factors (FGFs) are a family of growth factors critically involved in developmental, physiological, and pathological processes, including embryogenesis, angiogenesis, wound healing, and endocrine functions. In the liver, several FGFs are produced basally by hepatocytes and hepatic stellate cells (HSCs). Upon insult to the liver, expression of FGFs in HSCs is greatly upregulated, stimulating hepatocyte regeneration and growth. Various FGF isoforms have also been shown to directly induce HSC proliferation and activation thereby enabling autocrine and paracrine regulation of HSC function. Regulation of HSCs by the endocrine FGFs, namely, FGF15/19 and FGF21, has also recently been identified. With the ability to modulate HSC proliferation and transdifferentiation, targeting FGF signaling pathways constitutes a promising new therapeutic strategy to treat hepatic fibrosis.

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Fibroblast Growth Factor Signaling during Early Vertebrate Development

Endocrine Reviews ◽

10.1210/er.2003-0040 ◽

2004 ◽

Vol 26 (1) ◽

pp. 63-77 ◽

Cited By ~ 341

Author(s):

Ralph T. Böttcher ◽

Christof Niehrs

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Fibroblast Growth Factors ◽

Growth Factor Signaling ◽

Fibroblast Growth ◽

Vertebrate Development ◽

Fgf Signaling ◽

Fibroblast Growth Factor Signaling ◽

Cellular Processes ◽

Differentiation And Proliferation

Fibroblast growth factors (FGFs) have been implicated in diverse cellular processes including apoptosis, cell survival, chemotaxis, cell adhesion, migration, differentiation, and proliferation. This review presents our current understanding on the roles of FGF signaling, the pathways employed, and its regulation. We focus on FGF signaling during early embryonic processes in vertebrates, such as induction and patterning of the three germ layers as well as its function in the control of morphogenetic movements.

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The FGFRL1 Receptor Is Shed from Cell Membranes, Binds Fibroblast Growth Factors (FGFs), and Antagonizes FGF Signaling inXenopusEmbryos

Journal of Biological Chemistry ◽

10.1074/jbc.m109.058248 ◽

2009 ◽

Vol 285 (3) ◽

pp. 2193-2202 ◽

Cited By ~ 47

Author(s):

Florian Steinberg ◽

Lei Zhuang ◽

Michael Beyeler ◽

Roland E. Kälin ◽

Primus E. Mullis ◽

...

Keyword(s):

Growth Factors ◽

Cell Membranes ◽

Fibroblast Growth Factors ◽

Fibroblast Growth ◽

Fgf Signaling

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Signaling by Fibroblast Growth Factors (Fgf) and Fibroblast Growth Factor Receptor 2 (Fgfr2)–Activating Mutations Blocks Mineralization and Induces Apoptosis in Osteoblasts

The Journal of Cell Biology ◽

10.1083/jcb.149.6.1297 ◽

2000 ◽

Vol 149 (6) ◽

pp. 1297-1308 ◽

Cited By ~ 207

Author(s):

Alka Mansukhani ◽

Paola Bellosta ◽

Malika Sahni ◽

Claudio Basilico

Keyword(s):

Growth Factors ◽

Bone Growth ◽

Critical Role ◽

Fibroblast Growth Factors ◽

Apert Syndrome ◽

Osteoblastic Cell ◽

Fibroblast Growth ◽

Fgf Signaling ◽

Osteoblastic Cell Line ◽

Activating Mutations

Fibroblast growth factors (FGF) play a critical role in bone growth and development affecting both chondrogenesis and osteogenesis. During the process of intramembranous ossification, which leads to the formation of the flat bones of the skull, unregulated FGF signaling can produce premature suture closure or craniosynostosis and other craniofacial deformities. Indeed, many human craniosynostosis disorders have been linked to activating mutations in FGF receptors (FGFR) 1 and 2, but the precise effects of FGF on the proliferation, maturation and differentiation of the target osteoblastic cells are still unclear. In this report, we studied the effects of FGF treatment on primary murine calvarial osteoblast, and on OB1, a newly established osteoblastic cell line. We show that FGF signaling has a dual effect on osteoblast proliferation and differentiation. FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. To study the effect of craniosynostosis-linked mutations in osteoblasts, we introduced FGFR2 carrying either the C342Y (Crouzon syndrome) or the S252W (Apert syndrome) mutation in OB1 cells. Both mutations inhibited differentiation, while dramatically inducing apoptosis. Furthermore, we could also show that overexpression of FGF2 in transgenic mice leads to increased apoptosis in their calvaria. These data provide the first biochemical analysis of FGF signaling in osteoblasts, and show that FGF can act as a cell death inducer with distinct effects in proliferating and differentiating osteoblasts.

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Fibroblast Growth Factor (FGF): A Review

Dental Journal of Advance Studies ◽

10.1055/s-0038-1671960 ◽

2013 ◽

Vol 01 (02) ◽

pp. 091-094

Author(s):

Ram Gupta ◽

Manu Gupta ◽

Avnika Garg

Keyword(s):

Wound Healing ◽

Growth Factors ◽

Periodontal Regeneration ◽

Fibroblast Growth Factors ◽

Root Surface ◽

Matrix Proteins ◽

Fibroblast Growth ◽

Polypeptide Growth Factors ◽

Naturally Occurring ◽

Periodontal Wound Healing

AbstractIn order for periodontal regeneration to occur, progenitor cells must migrate to the denuded root surface, attach to it, proliferate and mature into an organized and functional fibrous attachment apparatus. Significant advances have been made during the last decade in understanding the factors controlling the migration, attachment and proliferation of cells. A group of naturally occurring molecules known as polypeptide growth factors in conjunction with certain matrix proteins, are key regulators of these biological events. Of these, the fibroblast growth factors (FGFs) appear to have an important role in periodontal wound healing. The purpose of this review is to summarize current information on these growth factors with emphasis on their potential implications in periodontal wound healing and regeneration.

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Fibroblast growth factors as regulators of central nervous system development and function

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00533.2002 ◽

2003 ◽

Vol 284 (4) ◽

pp. R867-R881 ◽

Cited By ~ 97

Author(s):

Rosanna Dono

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Growth Factors ◽

System Development ◽

Fibroblast Growth Factors ◽

Brain Structures ◽

Nervous System Development ◽

Adult Brain ◽

Fibroblast Growth ◽

Fgf Signaling

Fibroblast growth factors (FGFs) are multifunctional signaling proteins that regulate developmental processes and adult physiology. Over the last few years, important progress has been made in understanding the function of FGFs in the embryonic and adult central nervous system. In this review, I will first discuss studies showing that FGF signaling is already required during formation of the neural plate. Next, I will describe how FGF signaling centers control growth and patterning of specific brain structures. Finally, I will focus on the function of FGF signaling in the adult brain and in regulating maintenance and repair of damaged neural tissues.

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The role of fibroblast growth factors and their receptors in prostate cancer

Endocrine Related Cancer ◽

10.1677/erc.1.00535 ◽

2004 ◽

Vol 11 (4) ◽

pp. 709-724 ◽

Cited By ~ 212

Author(s):

B Kwabi-Addo ◽

M Ozen ◽

M Ittmann

Keyword(s):

Prostate Cancer ◽

Growth Factors ◽

Cancer Cells ◽

Cancer Progression ◽

Fibroblast Growth Factors ◽

Fibroblast Growth ◽

Fgf Signaling ◽

Prostate Cancer Progression ◽

Fgf Receptor

Prostate cancer is the most common malignancy in men in the USA and the second leading cause of cancer deaths. Fibroblast growth factors (FGFs), including FGF1 (acidic FGF), FGF2 (basic FGF), FGF6 and FGF8 are all expressed at increased levels in prostate cancer as paracrine and/or autocrine growth factors for the prostate cancer cells. In addition, increased mobilization of FGFs from the extracellular matrix in cancer tissues can increase the availability of FGFs to cancer cells. Prostate cancer epithelial cells express all four types of FGF receptors (FGFR-1 to -4) at variable frequencies. Expression of FGFR-1 and FGFR-4 is most closely linked to prostate cancer progression, while the role of FGFR-2 remains controversial. Activation of FGF receptors can activate multiple signal transduction pathways including the phospholipase Cγ, phosphatidyl inositol 3-kinase, mitogen-activated protein kinase and signal transducers and activators of transcription (STAT) pathways, all of which play a role in prostate cancer progression. Sprouty proteins can negatively regulate FGF signal transduction, potentially limiting the impact of FGF signaling in prostate cancer, but in a significant fraction of prostate cancers there is decreased expression of Sprouty1 mRNA and protein. The effects of increased FGF receptor signaling are wide ranging and involve both the cancer cells and surrounding stroma, including the vasculature. The net result of increased FGF signaling includes enhanced proliferation, resistance to cell death, increased motility and invasiveness, increased angiogenesis, enhanced metastasis, resistance to chemotherapy and radiation and androgen independence, all of which can enhance tumor progression and clinical aggressiveness. For this reason, the FGF signaling system it is an attractive therapeutic target, particularly since therapies targeting FGF receptors and/or FGF signaling can affect both the tumor cells directly and tumor angiogenesis. A number of approaches that could target FGF receptors and/or FGF receptor signaling in prostate cancer are currently being developed.

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