Summary: Fibroblast growth factor
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Fibroblast growth factor Edit Wikipedia article
|Fibroblast growth factor|
crystal structure analysis of the fgf10-fgfr2b complex
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. 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.
- Members FGF1 through FGF10 all bind fibroblast growth factor receptors (FGFRs). 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 (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".
- Human FGF18 is involved in cell development and morphogenesis in various tissues including cartilage.
- FGF15 through FGF23 were described later and not all their functions have been characterized. FGF15 is the mouse ortholog of human FGF19 (there is no human FGF15) 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.
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 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).
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 (first published report in 1974).
They then 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 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 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.
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.
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). 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 (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 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 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 (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. For example:
- FGF15 and FGF19 (FGF15/19) are produced by intestinal cells but act on FGFR4-expressing liver cells to downregulate the key gene (CYP7A1) 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.
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 (G-CSF)
- Granulocyte-macrophage colony stimulating factor (GM-CSF)
- Nerve growth factor (NGF)
- Erythropoietin (EPO)
- Thrombopoietin (TPO)
- Myostatin (GDF-8)
- Growth Differentiation factor-9 (GDF9)
- Finklestein S.P., Plomaritoglou A. (2001). "Growth factors". In Miller L.P., Hayes R.L., eds. Co-edited by Newcomb J.K. Head Trauma: Basic, Preclinical, and Clinical Directions. New York: Wiley. pp. 165â187. ISBN 0-471-36015-5.
- Blaber M, DiSalvo J, Thomas KA (February 1996). "X-ray crystal structure of human acidic fibroblast growth factor". Biochemistry 35 (7): 2086â94. doi:10.1021/bi9521755. PMID 8652550.
- Ornitz DM, Itoh N (2001). "Fibroblast growth factors". Genome Biol. 2 (3): reviews3005.1âreviews3005.12. doi:10.1186/gb-2001-2-3-reviews3005. PMC 138918. PMID 11276432.
- Olsen SK, Garbi M. et al. (2003). "Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs". J. Biol. Chem. 278 (36): 34226â36. doi:10.1074/jbc.M303183200. PMID 12815063.
- Itoh N, Ornitz DM (January 2008). "Functional evolutionary history of the mouse Fgf gene family". Dev. Dyn. 237 (1): 18â27. doi:10.1002/dvdy.21388. PMID 18058912.
- Moore, E.; Bendele, A.; Thompson, D.; Littau, A.; Waggie, K.; Reardon, B.; Ellsworth, J. (2005). "Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis". Osteoarthritis and Cartilage 13 (7): 623â631. doi:10.1016/j.joca.2005.03.003. PMID 15896984.
- Koga C, Adati N, Nakata K, Mikoshiba K, Furuhata Y, Sato S, Tei H, Sakaki Y, Kurokawa T (August 1999). "Characterization of a novel member of the FGF family, XFGF-20, in Xenopus laevis". Biochemical and Biophysical Research Communications 261 (3): 756â65. doi:10.1006/bbrc.1999.1039. PMID 10441498.
- Kirikoshi H, Sagara N, Saitoh T, Tanaka K, Sekihara H, Shiokawa K, Katoh M (August 2000). "Molecular cloning and characterization of human FGF-20 on chromosome 8p21.3-p22". Biochemical and Biophysical Research Communications 274 (2): 337â43. doi:10.1006/bbrc.2000.3142. PMID 10913340.
- Potthoff, M. J.; Kliewer, S. A.; Mangelsdorf, D. J. (2 February 2012). "Endocrine fibroblast growth factors 15/19 and 21: from feast to famine". Genes & Development 26 (4): 312â324. doi:10.1101/gad.184788.111. PMID 22302876.
- Fukumoto S (2008). "Actions and mode of actions of FGF19 subfamily members". Endocr. J. 55 (1): 23â31. doi:10.1507/endocrj.KR07E-002. PMID 17878606.
- Armelin HA (September 1973). "Pituitary extracts and steroid hormones in the control of 3T3 cell growth". Proc. Natl. Acad. Sci. U.S.A. 70 (9): 2702â6. Bibcode:1973PNAS...70.2702A. doi:10.1073/pnas.70.9.2702. PMC 427087. PMID 4354860.
- Gospodarowicz D (1974). "Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth". Nature 249 (453): 123â7. Bibcode:1974Natur.249..123G. doi:10.1038/249123a0. PMID 4364816.
- Arese M, Chen Y., et al. (1999). "Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals". Mol. Biol. Cell 10 (5): 1429â44. PMC 25296. PMID 10233154.
- Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z (1990). "Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis". Cancer Metastasis Rev 9 (3): 203â26. doi:10.1007/BF00046361. PMID 1705486.
- Green PJ, Walsh FS, Doherty P (1996). "Promiscuity of fibroblast growth factor receptors". BioEssays 18 (8): 639â46. doi:10.1002/bies.950180807. PMID 8760337.
- BÃ¶ttcher RT, Niehrs C. (2005). "Fibroblast growth factor signaling during early vertebrate development". Endocr. Rev. 26 (1): 63â77. doi:10.1210/er.2003-0040. PMID 15689573.
- Amaya E, Musci T.J. and Kirschner M.W. (1991). "Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos". Cell 66 (2): 257â270. doi:10.1016/0092-8674(91)90616-7. PMID 1649700.
- Borland C.Z., Schutzman J.L. and Stern M.J. (2001). "Fibroblast growth factor signaling in Caenorhabditis elegans". BioEssays 23 (12): 1120â1130. doi:10.1002/bies.10007. PMID 11746231.
- Coumoul X. and Deng C.X. (2003). "Roles of FGF receptors in mammalian development and congenital diseases". Birth Defects Res C Embryo Today 69 (4): 286â304. doi:10.1002/bdrc.10025. PMID 14745970.
- Sutherland D, Samakovlis C . and Krasnow M.A. (1996). "Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching". Cell 87 (6): 1091â1101. doi:10.1016/S0092-8674(00)81803-6. PMID 8978613.
- Stegmann, TJ (1999 May). "New approaches to coronary heart disease: induction of neovascularisation by growth factors.". BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 11 (5): 301â8. PMID 18031140.
- Vlodavsky Cao R, BrÃ¥kenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, Leboulch P, Cao Y (2003). "Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2". Nature Med 9 (5): 604â13. doi:10.1038/nm848. PMID 12669032.
- http://www.ncbi.nlm.nih.gov/pubmed/12845521, Reuss B, von Bohlen und Halbach O. 2003. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 313: 139-157.
- http://www.ncbi.nlm.nih.gov/pubmed/20581332, Zechel S, Werner S, Unsicker K, von Bohlen und Halbach O. 2010. Expression and functions of fibroblast growth factor 2 (FGF-2) in hippocampal formation. Neuroscientist 16: 357-373.
- Jones, SA (2012). "Physiology of FGF15/19.". Advances in experimental medicine and biology 728: 171â82. PMID 22396169.
- Razzaque, MS (2009 Nov). "The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis.". Nature reviews. Endocrinology 5 (11): 611â9. doi:10.1038/nrendo.2009.196. PMID 19844248.
- Murzin AG, Lesk AM, Chothia C (January 1992). "beta-Trefoil fold. Patterns of structure and sequence in the Kunitz inhibitors interleukins-1 beta and 1 alpha and fibroblast growth factors". J. Mol. Biol. 223 (2): 531â43. doi:10.1016/0022-2836(92)90668-A. PMID 1738162.
- Eriksson AE, Cousens LS, Weaver LH, Matthews BW (April 1991). "Three-dimensional structure of human basic fibroblast growth factor". Proc. Natl. Acad. Sci. U.S.A. 88 (8): 3441â5. Bibcode:1991PNAS...88.3441E. doi:10.1073/pnas.88.8.3441. PMC 51463. PMID 1707542.
- Gimenez-Gallego G, Rodkey J, Bennett C, Rios-Candelore M, DiSalvo J, Thomas K (December 1985). "Brain-derived acidic fibroblast growth factor: complete amino acid sequence and homologies". Science 230 (4732): 1385â8. Bibcode:1985Sci...230.1385G. doi:10.1126/science.4071057. PMID 4071057.
- Fibroblast Growth Factors at the US National Library of Medicine Medical Subject Headings (MeSH)
- FGF1 in Cosmetic Products
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Fibroblast growth factor Provide feedback
Fibroblast growth factors are a family of proteins involved in growth and differentiation in a wide range of contexts. They are found in a wide range of organisms, from nematodes to humans . Most share an internal core region of high similarity, conserved residues in which are involved in binding with their receptors. On binding, they cause dimerisation of their tyrosine kinase receptors leading to intracellular signalling. There are currently four known tyrosine kinase receptors for fibroblast growth factors. These receptors can each bind several different members of this family. Members of this family have a beta trefoil structure. Most have N-terminal signal peptides and are secreted. A few lack signal sequences but are secreted anyway; still others also lack the signal peptide but are found on the cell surface and within the extracellular matrix. A third group remain intracellular . They have central roles in development, regulating cell proliferation, migration and differentiation. On the other hand, they are important in tissue repair following injury in adult organisms .
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002348The interleukin-1 (IL1) and heparin-binding growth factor (HBGF) families share low sequence similarity (about 25% [PUBMED:1849658]) but have very similar structures. Coupled with the Kunitz-type soybean trypsin inhibitors (STI), they form a structural superfamily. Despite their structural correspondence, however, they show no sequence similarity to the STI family. The crystal structures of interleukin-1 beta and HBGF1 have been solved, showing both families to have the same 12-stranded beta-sheet structure [PUBMED:1738162]; the beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta-barrel [PUBMED:1707542, PUBMED:4071057]. 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.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||growth factor activity (GO:0008083)|
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Author:||Bateman A, Sonnhammer ELL|
|Number in seed:||77|
|Number in full:||1638|
|Average length of the domain:||113.10 aa|
|Average identity of full alignment:||32 %|
|Average coverage of the sequence by the domain:||52.07 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
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The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FGF domain has been found. There are 252 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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