Fibroblast growth factor

Source: Wikipedia, the free encyclopedia.

Fibroblast growth factors (FGF) are a family of

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]

Receptors

The mammalian

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

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

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

neural development,[16] and in mature tissues/systems angiogenesis, keratinocyte organization, and wound healing
processes.

FGF is critical during normal development of both

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)

autocrine manner, whereas HMW FGF2s are nuclear and exert activities through an intracrine
mechanism.

One important function of

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

chemotactic
effects on tissue remodelling.

During the development of the

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

JAK-STAT signalling pathway or the receptor tyrosine kinase
(RTK) pathway.

Members of the FGF19 subfamily (

endocrine fashion on far-away tissues, such as intestine, liver, kidney, adipose, and bone.[10]
For example:

Structure

The

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

References

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External links

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