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Fibroblast growth factor

Fibroblast growth factor

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Fibroblast growth factors, or FGFs, are a family of growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

s involved in angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

, wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...

, and embryonic development. The FGFs are heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

-binding proteins and interactions with cell-surface associated heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

 proteoglycans have been shown to be essential for FGF signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

. 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 molecule
Signaling molecule
A signaling molecule is a chemical involved in transmitting information between cells. Such molecules are released from the cell sending the signal, cross over the gap between cells by diffusion, and interact with specific receptors in another cell, triggering a response in that cell by activating...

s:
  • Members FGF1
    FGF1
    Heparin-binding growth factor 1 is a protein that in humans is encoded by the FGF1 gene.-Interactions:FGF1 has been shown to interact with CSNK2B, CSNK2A2, HSPA9, S100A13, Casein kinase 2, alpha 1, Fibroblast growth factor receptor 1, FIBP, Fibroblast growth factor receptor 4, Fibroblast growth...

     through FGF10 all bind fibroblast growth factor receptor
    Fibroblast growth factor receptor
    The fibroblast growth factor receptors are, as their name implies, receptors that bind to members of the fibroblast growth factor family of proteins. Some of these receptors are involved in pathological conditions...

    s (FGFRs). FGF1
    FGF1
    Heparin-binding growth factor 1 is a protein that in humans is encoded by the FGF1 gene.-Interactions:FGF1 has been shown to interact with CSNK2B, CSNK2A2, HSPA9, S100A13, Casein kinase 2, alpha 1, Fibroblast growth factor receptor 1, FIBP, Fibroblast growth factor receptor 4, Fibroblast growth...

     is also known as acidic, and FGF2 is also known as basic fibroblast growth factor.

  • Members FGF11
    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 family....

    , FGF12
    FGF12
    Fibroblast growth factor 12 is a protein that in humans is encoded by the FGF12 gene.-Further reading:...

    , FGF13
    FGF13
    Fibroblast growth factor 13 is a protein that in humans is encoded by the FGF13 gene.-Further reading:...

    , and FGF14
    FGF14
    Fibroblast growth factor 14 is a protein that in humans is encoded by the FGF14 gene.-Further reading:...

    , also known as FGF homologous factors 1-4 (FHF1-FHF4), 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".

  • Members FGF16
    FGF16
    Fibroblast growth factor 16 is a protein which in humans is encoded by the FGF16 gene.-Function:The protein encoded by this gene is a member of the fibroblast growth factor family...

     through FGF23 are newer and not as well characterized. FGF15 is the mouse ortholog of human FGF19
    FGF19
    Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene.-Further reading:...

     (hence there is no human FGF15).

  • Human FGF20
    FGF20
    Fibroblast growth factor 20 is a protein which in humans is encoded by the FGF20 gene.-Function:The protein encoded by this gene is a member of the fibroblast growth factor family...

     was identified based on its homology to Xenopus FGF-20 (XFGF-20).

  • In contrast to the local activity of the other FGFs, FGF15/FGF19
    FGF19
    Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene.-Further reading:...

    , FGF21
    FGF21
    Fibroblast growth factor 21 is a protein that in humans is encoded by the FGF21 gene. The protein encoded by this gene is a member of the fibroblast growth factor family...

     and FGF23 have more systemic effects.

Receptors


The mammalian fibroblast growth factor receptor
Fibroblast growth factor receptor
The fibroblast growth factor receptors are, as their name implies, receptors that bind to members of the fibroblast growth factor family of proteins. Some of these receptors are involved in pathological conditions...

 family has 4 members, FGFR1, FGFR2, FGFR3
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 .-Structure and function:-Disease linkage:...

, 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
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

 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 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 (keratinocyte growth factor, KGF) binds only to FGFR2b (KGFR).

The signaling complex at the cell surface is believed to be a ternary complex
Ternary complex
A Ternary complex refers to a protein complex containing three different molecules which are bound together. In structural biology ternary complex can be used to describe a crystal containing a protein with two small molecules bound, for example cofactor and substrate; or a complex formed between...

 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
Bioassay
Bioassay , or biological standardization is a type of scientific experiment. Bioassays are typically conducted to measure the effects of a substance on a living organism and are essential in the development of new drugs and in monitoring environmental pollutants...

 which caused fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s to proliferate (first published report in 1974).

They then further fractionated the extract using acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

ic and basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 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 amino acid identity but were determined to be distinct mitogens. Human FGF2 occurs in low molecular weight (LMW) and high molecular weight (HMW) isoforms.
LMW FGF2 is primarily cytoplasmic and functions in an autocrine
Autocrine signalling
Autocrine signaling is a form of signalling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on the same cell, leading to changes in the cell...

 manner, whereas HMW FGF2s are nuclear and exert activities through an intracrine
Intracrine
Intracrine refers to a hormone that acts inside a cell. Steroid hormones act through intracellular receptors and, thus, may be considered to be intracrines. In contrast, peptide or protein hormones, in general, act as endocrines, autocrines, or paracrines by binding to their receptors present on...

 mechanism.

Not long after FGF1 and FGF2 were isolated, another group isolated a pair of heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

-binding growth factors which they named HBGF-1 and HBGF-2, whilst a third group isolated a pair of growth factors that caused proliferation of cells in a bioassay
Bioassay
Bioassay , or biological standardization is a type of scientific experiment. Bioassays are typically conducted to measure the effects of a substance on a living organism and are essential in the development of new drugs and in monitoring environmental pollutants...

 containing blood vessel endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 cells which they called ECGF1
ECGF1
Thymidine phosphorylase is an enzyme that in humans is encoded by the TYMP gene.-External links:* -Further reading:...

 and ECGF2. These proteins were found to be identical to the acidic and basic FGFs described by Gospodarowicz, et al..

Function


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
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...

 induction, antero-posterior patterning, limb development
Limb development
Limb development in tetrapods — animals with four limbs — is an area of active research in developmental biology. Limb formation begins in the limb field, as a limb "bud." Fibroblast growth factor induces formation of an organizer, called the apical ectodermal ridge , which guides further...

, neural induction and neural development
Neural development
Neural development comprises the processes that generate, shape, and reshape the nervous system, from the earliest stages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to address the underlying mechanisms...

, and in mature tissues/systems angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

, keratinocyte organization, and wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...

 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.

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
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

, the growth of new blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s from the pre-existing vasculature. FGF1 and FGF2 are more potent angiogenic factors than vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....

 (VEGF) or platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...

 (PDGF).

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
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...

, which fills up a wound space/cavity early in the wound healing process. FGF7 and FGF10 (also known as Keratinocyte Growth Factor
Keratinocyte Growth Factor
The Keratinocyte Growth Factor , also known as FGF7, is a growth factor present in the epithelialization-phase of wound healing. In this phase, keratinocytes are covering the wound, forming the epithelium....

s 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 remodeling.

During development of the central nervous system, FGFs play important roles in neurogenesis, axon growth, and differentiation. 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 FGF-2. In addition, FGF-1 and FGF-2 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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

 of tissues that contain heparan sulfate proteoglycans. This allows them to act locally in a paracrine fashion. However, the FGF19 subfamily (including FGF19, FGF21, and FGF23) which binds less tightly to heparan sulfates can act in an endocrine fashion on far away tissues, such as intestine, liver, kidney, adipose, and bone. For example, FGF19 is produced by intestinal cells but acts on FGFR4-expressing liver cells to downregulate key genes in the bile acid synthase pathway; FGF23 is produced by bone but acts on FGFR1-expressing kidney cells to regulate the synthesis of vitamin D and in turn affect calcium homeostasis.

Structure


The crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...

s of HBGF1 has been solved, and found to be related to interleukin 1-beta
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...

, both families to have the same 12-stranded beta-sheet structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...

, the beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta-barrel. The beta-sheets are generally 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 (G-CSF)
  • granulocyte-macrophage colony stimulating factor (GM-CSF)
  • nerve growth factor
    Nerve growth factor
    Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...

     (NGF)
  • neurotrophins
  • erythropoietin
    Erythropoietin
    Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...

     (EPO)
  • thrombopoietin
    Thrombopoietin
    Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....

     (TPO)
  • myostatin
    Myostatin
    Myostatin is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor...

     (GDF-8)
  • Growth Differentiation factor-9
    Growth differentiation factor-9
    Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene.GDF9 plays an important role in the development of primary follicles in the ovary...

    (GDF9)

External links