Family of proteins involved in anatomical development
Fibroblast growth factors (FGF) are a family of
cell signallingproteins produced by
macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These
growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to
heparin and to
heparan sulfate. Thus, some are sequestered in the
extracellular matrix of tissues that contains
heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.[1]
Families
In humans, 23 members of the FGF family have been identified, all of which are structurally related
signaling molecules:[2][3][4]
Members
FGF11,
FGF12,
FGF13, and
FGF14, also known as FGF homologous factors 1-4 (FHF1-FHF4), have been shown to have distinct functions compared to the FGFs. Although these factors possess remarkably similar sequence homology, they do not bind
FGFRs and are involved in intracellular processes unrelated to the FGFs.[5] This group is also known as the intracellular fibroblast growth factor subfamily (iFGF).[6]
Human
FGF18 is involved in cell development and morphogenesis in various tissues including cartilage.[7]
Human
FGF20 was identified based on its homology to Xenopus FGF-20 (XFGF-20).[8][9]
FGF15 through
FGF23 were described later and functions are still being characterized.
FGF15 is the mouse ortholog of human
FGF19 (there is no human FGF15) and, where their functions are shared, they are often described as
FGF15/19.[10] In contrast to the local activity of the other FGFs, FGF15/19,
FGF21 and
FGF23 have
hormonal systemic effects.[10][11]
Receptors
The mammalian
fibroblast growth factor receptor family has 4 members,
FGFR1,
FGFR2,
FGFR3, and
FGFR4. The FGFRs consist of three extracellular immunoglobulin-type domains (D1-D3), a single-span trans-membrane domain and an intracellular split
tyrosine kinase domain. FGFs interact with the D2 and D3 domains, with the D3 interactions primarily responsible for ligand-binding specificity (see below). Heparan sulfate binding is mediated through the D3 domain. A short stretch of acidic amino acids located between the D1 and D2 domains has auto-inhibitory functions. This 'acid box' motif interacts with the heparan sulfate binding site to prevent receptor activation in the absence of FGFs.[12]
Alternate mRNA splicing gives rise to 'b' and 'c' variants of FGFRs 1, 2 and 3. Through this mechanism, seven different signalling FGFR sub-types can be expressed at the cell surface. Each FGFR binds to a specific subset of the FGFs. Similarly, most FGFs can bind to several different FGFR subtypes. FGF1 is sometimes referred to as the 'universal ligand' as it is capable of activating all 7 different FGFRs. In contrast, FGF7 (keratinocyte growth factor, KGF) binds only to FGFR2b (KGFR).[13]
The signalling complex at the cell surface is believed to be a
ternary complex formed between two identical FGF ligands, two identical FGFR subunits, and either one or two
heparan sulfate chains.
History
A
mitogenic growth factor activity was found in
pituitary extracts by Armelin in 1973[14] and further work by Gospodarowicz as reported in 1974 described a more defined isolation of proteins from cow brain extract which, when tested in a
bioassay that caused
fibroblasts to
proliferate, led these investigators to apply the name "fibroblast growth factor."[15] In 1975, they further
fractionated the extract using
acidic and
basic pH and isolated two slightly different forms that were named "acidic fibroblast growth factor" (FGF1) and "basic fibroblast growth factor" (FGF2). These proteins had a high degree of sequence homology among their amino acid chains, but were determined to be distinct proteins.
Not long after FGF1 and FGF2 were isolated, another group of investigators isolated a pair of
heparin-binding growth factors that they named HBGF-1 and HBGF-2, while a third group isolated a pair of growth factors that caused
proliferation of cells in a
bioassay containing blood vessel
endothelium cells, which they called
ECGF1 and ECGF2. These independently discovered proteins were eventually demonstrated to be the same sets of molecules, namely FGF1, HBGF-1 and ECGF-1 were all the same acidic fibroblast growth factor described by Gospodarowicz, et al., while FGF2, HBGF-2, and ECGF-2 were all the same basic fibroblast growth factor.[1]
Functions
FGFs are multifunctional proteins with a wide variety of effects; they are most commonly
mitogens but also have regulatory, morphological, and endocrine effects. They have been alternately referred to as "
pluripotent" growth factors and as "promiscuous" growth factors due to their multiple actions on multiple cell types.[16][17] Promiscuous refers to the biochemistry and pharmacology concept of how a variety of molecules can bind to and elicit a response from single receptor. In the case of FGF, four receptor subtypes can be activated by more than twenty different FGF
ligands. Thus the functions of FGFs in developmental processes include
mesoderm induction, anterior-posterior patterning,[8]limb development, neural induction and
neural development,[18] and in mature tissues/systems
angiogenesis,
keratinocyte organization, and
wound healing processes.
FGF is critical during normal development of both
vertebrates and
invertebrates and any irregularities in their function leads to a range of developmental defects.[19][20][21][22]
FGFs secreted by
hypoblasts during avian
gastrulation play a role in stimulating a
Wnt signaling pathway that is involved in the differential movement of
Koller's sickle cells during formation of the
primitive streak.[23] Left,
angiography of the newly formed vascular network in the region of the front wall of the left ventricle. Right, analysis quantifying the angiogenic effect.[24]
While many FGFs can be secreted by cells to act on distant targets, some FGF act locally within a tissue, and even within a cell. Human FGF2 occurs in low molecular weight (LMW) and high molecular weight (HMW)
isoforms.[25] LMW FGF2 is primarily cytoplasmic and functions in an
autocrine manner, whereas HMW FGF2s are nuclear and exert activities through an
intracrine mechanism.
As well as stimulating blood vessel growth, FGFs are important players in wound healing. FGF1 and FGF2 stimulate
angiogenesis and the proliferation of
fibroblasts that give rise to
granulation tissue, which fills up a wound space/cavity early in the wound-healing process.
FGF7 and
FGF10 (also known as
keratinocyte growth factors KGF and KGF2, respectively) stimulate the repair of injured skin and mucosal tissues by stimulating the proliferation, migration and differentiation of
epithelial cells, and they have direct
chemotactic effects on tissue remodelling.
During the development of the
central nervous system, FGFs play important roles in
neural stem cell proliferation,
neurogenesis,
axon growth, and differentiation. FGF signaling is important in promoting surface area growth of the developing
cerebral cortex by reducing
neuronal differentiation and hence permitting the self-renewal of cortical progenitor cells, known as
radial glial cells,[27] and FGF2 has been used to induce artificial
gyrification of the
mouse brain.[28] Another FGF family member,
FGF8, regulates the size and positioning of the functional areas of the cerebral cortex (
Brodmann areas).[29][30]
FGFs are also important for maintenance of the adult brain. Thus, FGFs are major determinants of neuronal survival both during development and during adulthood.[31]
Adult neurogenesis within the
hippocampus e.g. depends greatly on FGF2. In addition, FGF1 and FGF2 seem to be involved in the regulation of
synaptic plasticity and processes attributed to learning and memory, at least in the hippocampus.[31]
Members of the FGF19 subfamily (
FGF15,
FGF19,
FGF21, and
FGF23) bind less tightly to heparan sulfates, and so can act in an
endocrine fashion on far-away tissues, such as intestine, liver, kidney, adipose, and bone.[10] For example:
FGF15 and FGF19 (FGF15/19) are produced by intestinal cells but act on
FGFR4-expressing liver cells to downregulate the key gene (
CYP7A1) in the bile acid synthesis pathway.[32]
FGF23 is produced by bone but acts on
FGFR1-expressing kidney cells to regulate the synthesis of vitamin D and phosphate homeostasis.[33]
Structure
The
crystal structures of
FGF1 have been solved and found to be related to
interleukin 1-beta. Both families have the same
beta trefoil fold consisting of 12-stranded
beta-sheetstructure, with the beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel
beta-barrel.[34][35][36] In general, the beta-sheets are well-preserved and the crystal structures superimpose in these areas. The intervening loops are less well-conserved - the loop between beta-strands 6 and 7 is slightly longer in interleukin-1 beta.
Clinical applications
Dysregulation of the FGF signalling system underlies a range of diseases associated with the increased FGF expression. Inhibitors of FGF signalling have shown clinical efficacy.[37] Some FGF ligands (particularly FGF2) have been demonstrated to enhance tissue repair (e.g. skin burns, grafts, and ulcers) in a range of clinical settings.[38]
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^Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z (Nov 1990). "Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis". Cancer and Metastasis Reviews. 9 (3): 203–26.
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^Cao R, Bråkenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, et al. (May 2003). "Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2". Nature Medicine. 9 (5): 604–13.
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