Fibroblast growth factor

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Fibroblast growth factors (FGF) are a family of cell signalling proteins 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]

Contents

Families

In humans, 23 members of the FGF family have been identified, all of which are structurally related signaling molecules: [2] [3] [4]

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.

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 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 [12] 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." [13] 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. [14] [15] 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, [16] 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. [17] [18] [19] [20]

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. [21] 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. [22]

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. [23] LMW FGF2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF2s are nuclear and exert activities through an intracrine mechanism.

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 (VEGF) or platelet-derived growth factor (PDGF). [24] FGF1 has been shown in clinical experimental studies to induce angiogenesis in the heart. [22]

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, [25] and FGF2 has been used to induce artificial gyrification of the mouse brain. [26] Another FGF family member, FGF8, regulates the size and positioning of the functional areas of the cerebral cortex (Brodmann areas). [27] [28]

FGFs are also important for maintenance of the adult brain. Thus, FGFs are major determinants of neuronal survival both during development and during adulthood. [29] 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. [29]

The 15 exparacrine FGFs are secreted proteins that bind heparan sulfate and can, therefore, be bound to 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 signalling pathway or the receptor tyrosine kinase (RTK) pathway.

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:

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-sheet structure, with the beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta-barrel. [32] [33] [34] 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. [35] 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. [36]

See also

Related Research Articles

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 regulating a variety of cellular processes.

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Basic fibroblast growth factor</span> Growth factor and signaling protein otherwise known as 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 (FGFR) proteins, themselves a family of closely related molecules. Fibroblast growth factor protein was first purified in 1975; soon thereafter three variants were isolated: 'basic FGF' (FGF2); Heparin-binding growth factor-2; and Endothelial cell growth factor-2. Gene sequencing revealed that this group is the same FGF2 protein and is a member of a family of FGF proteins.

<span class="mw-page-title-main">FGF1</span> Protein-coding gene in the species Homo sapiens

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-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1. Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

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 kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.

<span class="mw-page-title-main">CTGF</span> Protein found in humans

CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

<span class="mw-page-title-main">Fibroblast growth factor receptor 2</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 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 keratinocyte growth factor (KGF), 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.

<span class="mw-page-title-main">Syndecan</span>

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. they are proteoglycans, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.

<span class="mw-page-title-main">Fibroblast growth factor receptor 1</span> Protein-coding gene in the species Homo sapiens

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 growth factor family. FGFR1 has been shown to be associated with Pfeiffer syndrome, and clonal eosinophilias.

<span class="mw-page-title-main">Fibroblast growth factor receptor 4</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334.

<span class="mw-page-title-main">Syndecan-4</span> Protein-coding gene in the species Homo sapiens

Syndecan-4 is a protein that in humans is encoded by the SDC4 gene. Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. Syndecans are the best-characterized plasma membrane proteoglycans. Their intracellular domain of membrane-spanning core protein interacts with actin cytoskeleton and signaling molecules in the cell cortex. Syndecans are normally found on the cell surface of fibroblasts and epithelial cells. Syndecans interact with fibronectin on the cell surface, cytoskeletal and signaling proteins inside the cell to modulate the function of integrin in cell-matrix adhesion. Also, syndecans bind to FGFs and bring them to the FGF receptor on the same cell. As a co-receptor or regulator, mutated certain proteoglycans could cause severe developmental defects, like disordered distribution or inactivation of signaling molecules.

<span class="mw-page-title-main">FGF10</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.

<span class="mw-page-title-main">FGF19</span> Protein-coding gene in the species Homo sapiens

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 in chronic bile acid diarrhea and in certain metabolic disorders.

<span class="mw-page-title-main">NUDT6</span> Protein-coding gene in the species Homo sapiens

Nucleoside diphosphate-linked moiety X motif 6 is a protein that in humans is encoded by the NUDT6 gene.

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. They are often referred together 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 so are often referred to as FGF15/19 or as FGF15/FGF19.

References

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