Fibroblast Growth Factor
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Fibroblast growth factors (FGF) are a family of cell signalling
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s 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 A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...
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 Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
. Thus, some are sequestered in the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
of tissues that contains
heparan sulfate proteoglycan Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ...
s and are released locally upon injury or tissue remodeling.


Families

In humans, 23 members of the FGF family have been identified, all of which are ''structurally'' related
signaling molecule In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a Cell (biology), cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property ...
s: * Members
FGF1 Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the ''FGF1'' gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycos ...
through
FGF10 Fibroblast growth factor 10 is a protein that in humans is encoded by the ''FGF10'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell s ...
all bind fibroblast growth factor receptors (FGFRs).
FGF1 Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the ''FGF1'' gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycos ...
is also known as ''acidic fibroblast growth factor'', and
FGF2 Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
is also known as ''basic fibroblast growth factor''. * Members
FGF11 Fibroblast growth factor 11 also known as FGF11 is a human gene. The protein encoded by this gene is a member of the intracellular fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macr ...
,
FGF12 Fibroblast growth factor 12 is a protein that in humans is encoded by the ''FGF12'' gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival act ...
, FGF13, and
FGF14 Fibroblast growth factor 14 is a biologically active protein that in humans is encoded by the ''FGF14'' gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and ...
, 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. This group is also known as "iFGF". *Human
FGF18 Fibroblast growth factor 18 is a protein that in humans is encoded by the ''FGF18'' gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival acti ...
is involved in cell development and morphogenesis in various tissues including cartilage. * Human FGF20 was identified based on its homology to ''Xenopus'' FGF-20 (XFGF-20). *
FGF15 Fibroblast growth factor 15 is a protein in mouse encoded by the ''Fgf15'' gene. It is a member of the fibroblast growth factor (FGF) family but, like FGF19, FGF21 and FGF23, has endocrine functions. FGF19 is the orthologous protein in humans. ...
through
FGF23 Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF23 decreases rea ...
were described later and functions are still being characterized.
FGF15 Fibroblast growth factor 15 is a protein in mouse encoded by the ''Fgf15'' gene. It is a member of the fibroblast growth factor (FGF) family but, like FGF19, FGF21 and FGF23, has endocrine functions. FGF19 is the orthologous protein in humans. ...
is the mouse ortholog of human
FGF19 Fibroblast growth factor 19 is a protein that in humans is encoded by the ''FGF19'' gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor ...
(there is no human FGF15) and, where their functions are shared, they are often described as
FGF15/19 FGF15/19 refers to two orthologous fibroblast growth factors which share 50% aminoacid identity and have similar functions. FGF15 was described in the mouse; FGF19 was found in humans and other species. They share physiological functions and ...
. In contrast to the local activity of the other FGFs, FGF15/19,
FGF21 Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the ''FGF21'' gene. Together with FGF19 ( FGF15 in rodents) and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth ...
and
FGF23 Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF23 decreases rea ...
have
hormonal A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required f ...
systemic effects.


Receptors

The mammalian fibroblast growth factor receptor family has 4 members,
FGFR1 Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast ...
,
FGFR2 Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 (cluster of differentiation 332) is a protein that in humans is encoded by the ''FGFR2'' gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor. The protein ...
,
FGFR3 Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the ''FGFR3'' gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location q16.3, is expressed in ...
, and
FGFR4 Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the ''FGFR4'' gene. FGFR4 has also been designated as CD334 (cluster of differentiation 334). The protein encoded by this gene is a member of the fibroblast growth fact ...
. The FGFRs consist of three extracellular immunoglobulin-type domains (D1-D3), a single-span trans-membrane domain and an intracellular split
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
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. 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). The signalling complex at the cell surface is believed to be a
ternary complex A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, for example ...
formed between two identical FGF ligands, two identical FGFR subunits, and either one or two
heparan Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
sulfate chains.


History

A
mitogen A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
ic growth factor activity was found in
pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...
extracts by Armelin in 1973 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 A bioassay is an analytical method to determine the concentration or potency of a substance by its effect on living animals or plants (''in vivo''), or on living cells or tissues(''in vitro''). A bioassay can be either quantal or quantitative, dir ...
that caused fibroblasts to proliferate, led these investigators to apply the name "fibroblast growth factor." In 1975, they further
fractionated Fractionation is a separation process in which a certain quantity of a mixture (of gases, solids, liquids, enzymes, or isotopes, or a suspension) is divided during a phase transition, into a number of smaller quantities ( fractions) in which t ...
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 A bioassay is an analytical method to determine the concentration or potency of a substance by its effect on living animals or plants (''in vivo''), or on living cells or tissues(''in vitro''). A bioassay can be either quantal or quantitative, dir ...
containing blood vessel
endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...
cells, which they called
ECGF1 TYMP is a gene that encodes for the enzyme thymidine phosphorylase. The ''TYMP'' gene is also known as ECGF1 (endothelial cell growth factor 1, platelet-derived) and MNGIE due to its role in Mitochondrial neurogastrointestinal encephalopathy synd ...
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.


Functions

FGFs are multifunctional proteins with a wide variety of effects; they are most commonly
mitogens A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
but also have regulatory, morphological, and endocrine effects. They have been alternately referred to as "
pluripotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...
" 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
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
s. Thus the functions of FGFs in developmental processes include mesoderm induction, anterior-posterior patterning,
limb development Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb. Limb formation begins in the morphogenetic limb field, as mes ...
, neural induction and neural development, and in mature tissues/systems angiogenesis,
keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
organization, and
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
processes. FGF is critical during normal development of both
vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
and
invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordat ...
and any irregularities in their function leads to a range of developmental defects. FGFs secreted by
hypoblast In amniote embryology, the hypoblast, is one of two distinct layers arising from the inner cell mass in the mammalian blastocyst, or from the blastodisc in reptiles and birds. The hypoblast gives rise to the yolk sac, which in turn gives ris ...
s during avian gastrulation play a role in stimulating a
Wnt signaling pathway The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
that is involved in the differential movement of
Koller's sickle In avian gastrulation, Koller's sickle is a local thickening of cells at the posterior edge of the upper layer of the area pellucida called the epiblast. Koller's sickle is crucial for avian development, due to its critical role in inducing the di ...
cells during formation of the primitive streak.Gilbert SF. Developmental Biology. 10th edition. Sunderland (MA): Sinauer Associates; 2014. Early Development in Birds. Print Left,
angiography Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is perfor ...
of the newly formed vascular network in the region of the front wall of the left ventricle. Right, analysis quantifying the angiogenic effect. 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)
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
s. LMW FGF2 is primarily cytoplasmic and functions in an
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...
manner, whereas HMW FGF2s are nuclear and exert activities through an
intracrine Intracrine refers to a hormone that acts inside a cell, regulating intracellular events. In simple terms it means that the cell stimulates itself by cellular production of a factor that acts within the cell. Steroid hormones act through intracellu ...
mechanism. One important function of
FGF1 Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the ''FGF1'' gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycos ...
and
FGF2 Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
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 vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s from the pre-existing
vasculature The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. FGF1 and FGF2 are more potent angiogenic factors than
vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF) or
platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
(PDGF). 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 Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any siz ...
, which fills up a wound space/cavity early in the wound-healing process.
FGF7 Keratinocyte growth factor is a protein that in humans is encoded by the ''FGF7'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell surv ...
and
FGF10 Fibroblast growth factor 10 is a protein that in humans is encoded by the ''FGF10'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell s ...
(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 Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
effects on tissue remodelling. During the development of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
, FGFs play important roles in
neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...
proliferation, neurogenesis,
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
growth, and differentiation. FGF signaling is important in promoting surface area growth of the developing
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...
by reducing
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
al differentiation and hence permitting the self-renewal of cortical progenitor cells, known as
radial glial cell Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ...
s, and FGF2 has been used to induce artificial
gyrification Gyrification is the process of forming the characteristic folds of the cerebral cortex. The peak of such a fold is called a ''gyrus'' (pl. ''gyri''), and its trough is called a '' sulcus'' (pl. ''sulci''). The neurons of the cerebral cortex re ...
of the
mouse brain The mouse brain refers to the brain of Mus musculus. Various brain atlases exist. For reasons of reproducibility, genetically characterized, stable strains like C57BL/6 were chosen to produce high-resolution images and databases. Well known onl ...
. Another FGF family member,
FGF8 Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the ''FGF8'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic an ...
, regulates the size and positioning of the functional areas of the cerebral cortex (
Brodmann area A Brodmann area is a region of the cerebral cortex, in the human or other primate brain, defined by its cytoarchitecture, or histological structure and organization of cells. History Brodmann areas were originally defined and numbered by th ...
s). 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 The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
e.g. depends greatly on FGF2. In addition, FGF1 and FGF2 seem to be involved in the regulation of
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits ...
and processes attributed to learning and memory, at least in the hippocampus. The 15 exparacrine FGFs are secreted proteins that bind
heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
and can, therefore, be bound to the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
of tissues that contain heparan sulfate proteoglycans. This local action of FGF proteins is classified as
paracrine signalling Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
, most commonly through the JAK-STAT signalling pathway or the
receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
(RTK) pathway. Members of the FGF19 subfamily (
FGF15 Fibroblast growth factor 15 is a protein in mouse encoded by the ''Fgf15'' gene. It is a member of the fibroblast growth factor (FGF) family but, like FGF19, FGF21 and FGF23, has endocrine functions. FGF19 is the orthologous protein in humans. ...
,
FGF19 Fibroblast growth factor 19 is a protein that in humans is encoded by the ''FGF19'' gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor ...
,
FGF21 Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the ''FGF21'' gene. Together with FGF19 ( FGF15 in rodents) and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth ...
, and
FGF23 Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF23 decreases rea ...
) 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 (FGF15/19) are produced by intestinal cells but act on
FGFR4 Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the ''FGFR4'' gene. FGFR4 has also been designated as CD334 (cluster of differentiation 334). The protein encoded by this gene is a member of the fibroblast growth fact ...
-expressing liver cells to downregulate the key gene ( CYP7A1) in the bile acid synthesis pathway. *
FGF23 Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF23 decreases rea ...
is produced by bone but acts on
FGFR1 Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast ...
-expressing kidney cells to regulate the synthesis of vitamin D and phosphate homeostasis.


Structure

The
crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric patterns ...
s of
FGF1 Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the ''FGF1'' gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycos ...
have been solved and found to be related to interleukin 1-beta. Both families have the same
beta trefoil fold In molecular biology the β trefoil fold is a protein fold that consists of six beta hairpins, each formed by two beta strands. Together these form a beta barrel with a triangular "cap", each consisting of three hairpins. Overall, this structure ...
consisting of 12-stranded
beta-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a ge ...
structure, with the beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel
beta-barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...
. 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. 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.


See also

*
Receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
* Granulocyte-colony stimulating factor (G-CSF) *
Granulocyte-macrophage colony stimulating factor Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts ...
(GM-CSF) * Nerve growth factor (NGF) *
Neurotrophins Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth facto ...
* Erythropoietin (EPO) *
Thrombopoietin Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene. Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
(TPO) *
Myostatin Myostatin (also known as growth differentiation factor 8, abbreviated GDF8) is a protein that in humans is encoded by the ''MSTN'' gene. Myostatin is a myokine that is produced and released by myocytes and acts on muscle cells to inhibit muscle ...
(GDF8) * Growth differentiation factor 9 (GDF9) *
Gyrification Gyrification is the process of forming the characteristic folds of the cerebral cortex. The peak of such a fold is called a ''gyrus'' (pl. ''gyri''), and its trough is called a '' sulcus'' (pl. ''sulci''). The neurons of the cerebral cortex re ...
* Neurogenesis


References


External links

*
FGF5 in Hair Tonic Products

FGF1 in Cosmetic Products
{{DEFAULTSORT:Fibroblast Growth Factor Protein domains Growth factors Morphogens World Anti-Doping Agency prohibited substances