Fibroblast growth factors, or FGFs, are a family of growth factors, with members
involved in angiogenesis, wound healing, embryonic development and various
endocrine signaling pathways. The FGFs are heparin-binding proteins and
interactions with cell-surface-associated heparan sulfate
proteoglycans have been shown to be essential for FGF signal transduction.
FGFs are key players in the processes of proliferation and differentiation of
wide variety of cells and tissues. Families
In humans, 22 members of the FGF family have been identified, all of which are
structurally related signaling molecules:
Members FGF1 through FGF10 all bind fibroblast growth factor receptors. FGF1
is also known as acidic, and FGF2 is also known as basic fibroblast growth
factor. Members FGF11, FGF12, FGF13, and FGF14,
also known as FGF homologous factors 1-4, have been shown to have distinct
functional differences 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. This group is also known as
"iFGF". Human FGF18 is involved in cell
development and morphogenesis in various tissues including cartilage.
Human FGF20 was identified based on its homology to Xenopus FGF-20.
FGF15 through FGF23 were described later and functions are still being
characterized. FGF15 is the mouse ortholog of human FGF19 and, where their
functions are shared, they are often described as FGF15/19. In contrast to
the local activity of the other FGFs, FGF15/19, FGF21 and FGF23 have systemic
effects. 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, 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. 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.
Alternate mRNA splicing gives rise to 'b' and 'c' variants of FGFRs 1, 2 and
3. Through this mechanism seven different signaling 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 binds only to FGFR2b.
The signaling 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 Fibroblast growth factor was found in
pituitary extracts by Armelin in 1973 and then was also found in a cow brain
extract by Gospodarowicz, et al., and tested in a bioassay that caused
fibroblasts to proliferate. They then further fractionated the
extract using acidic and basic pH and isolated two slightly different forms
that were named "acidic fibroblast growth factor" and "basic fibroblast
growth factor". These proteins had a high degree of amino acid identity but
were determined to be distinct mitogens. Human FGF2 occurs in low molecular
weight and high molecular weight isoforms. LMW FGF2 is primarily
cytoplasmic and functions in an autocrine manner, whereas HMW FGF2s are
nuclear and exert activities through an intracrine mechanism.
Not long after FGF1 and FGF2 were isolated, another group 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 proteins were found to be identical to the acidic
and basic FGFs described by Gospodarowicz, et al.
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. 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, antero-posterior patterning, limb development, neural induction and
neural development, 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. 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. One important function of FGF1 and FGF2
is the promotion of endothelial cell proliferation and the physical
organization of endothelial cells into tube-like structures. They thus promote
angiogenesis, the growth of new blood vessels from the pre-existing
vasculature. FGF1 and FGF2 are more potent angiogenic factors than vascular
endothelial growth factor or platelet-derived growth factor. FGF1 has
been shown in clinical experimental studies to induce angiogenesis in the
heart. 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 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 remodeling. 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, and FGF2 has been
used to induce artificial gyrification of the mouse brain. Another FGF family
member, FGF8, regulates the size and positioning of the functional areas of
the cerebral cortex. FGFs are also important for maintenance of the adult
brain. Thus, FGFs are major determinants of neuronal survival both during
development and during adulthood. 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. Most FGFs are secreted proteins that
bind heparan sulfates and can, therefore, be caught up in the
extracellular matrix of tissues that contain heparan sulfate proteoglycans.
This local action of FGF proteins is classified as paracrine signalling, most
commonly through the JAK-STAT signaling pathway or the Receptor tyrosine kinase
pathway. Members of the FGF19 subfamily 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. For example:
FGF15 and FGF19 are produced by intestinal cells but act on
FGFR4-expressing liver cells to downregulate the key gene in the bile
acid synthesis pathway. FGF23 is produced by bone but acts on
FGFR1-expressing kidney cells to regulate the synthesis of vitamin D and
phosphate homeostasis. Structure
The crystal structures of HBGF1 have been solved and found to be related to
interleukin 1-beta. Both families have the same 12-stranded beta-sheet
structure, and the beta-sheets are arranged in 3 similar lobes around a
central axis, 6 strands forming an anti-parallel beta-barrel. 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.
See also Granulocyte-colony stimulating factor
Granulocyte-macrophage colony stimulating factor
Nerve growth factor Neurotrophins
Erythropoietin Thrombopoietin
Myostatin Growth Differentiation factor-9
Gyrification References
External links Fibroblast Growth Factors at the US
National Library of Medicine Medical Subject Headings
FGF1 in Cosmetic Products This article incorporates text from the
public domain Pfam and InterPro IPR002348