Fibroblast growth factor receptor

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Fibroblast growth factor receptor
Identifiers
SymbolFGFR
InterPro IPR016248
Membranome 1201

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.

Contents

Structure

The fibroblast growth factor receptors consist of an extracellular ligand domain composed of three immunoglobulin-like domains, a single transmembrane helix domain, and an intracellular domain with tyrosine kinase activity. These receptors bind fibroblast growth factors, members of the largest family of growth factor ligands, comprising 22 members. [1] [2]

The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR. [3] These isoforms vary in their ligand-binding properties and kinase domains, however all share the common extracellular region composed of three immunoglobulin(Ig)-like domains (D1-D3), and thus belong to the immunoglobulin superfamily. [4]

The three immunoglobin(Ig)-like domains—D1, D2, and D3—present a stretch of acidic amino acids ("the acid box") between D1 and D2. [5] This "acid box" can participate in the regulation of FGF binding to the FGFR. Immunoglobulin-like domains D2 and D3 are sufficient for FGF binding. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor (i.e., FGF1, which binds all seven principal FGFRs [6] ). FGF7, however, can only activate FGFR2b, [3] and FGF18 was recently shown to activate FGFR3. [7]

A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain and one isoform, FGFR5γ, and only contains the extracellular domains D1 and D2. [8] The FGFRs are known to dimerize as heterodimers and homodimers.

Genes

So far, five distinct membrane FGFR have been identified in vertebrates and all of them belong to the tyrosine kinase superfamily (FGFR1 to FGFR4).

As a drug target

The FGF/FGFR signalling pathway is involved in a variety of cancers. [9]

There are non-selective FGFR inhibitors that act on all of FGFR1-4 and other proteins, and some selective FGFR inhibitors for some/all of FGFR1-4. [10] Selective FGFR inhibitors include AZD4547, BGJ398, JNJ42756493, and PD173074. [10]

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

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.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, 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 a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

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.

<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">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.

<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.

<span class="mw-page-title-main">Platelet-derived growth factor receptor</span> Protein family

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.

<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.

<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 3</span> Gene involved in the most common form of dwarfism

Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333. The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<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">FGF5</span> Mammalian protein found in Homo sapiens

Fibroblast growth factor 5 is a protein that in humans is encoded by the FGF5 gene.

<span class="mw-page-title-main">Fibroblast growth factor receptor-like 1</span> Protein found in humans

Fibroblast growth factor receptor-like 1 is a protein that in humans is encoded by the FGFRL1 gene.

Collagen receptors are membrane proteins that bind the extracellular matrix protein collagen, the most abundant protein in mammals. They control mainly cell proliferation, migration and adhesion, coagulation cascade activation and they affect ECM structure by regulation of MMP.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

<span class="mw-page-title-main">Immunoglobulin I-set domain</span>

I-set domains are found in several cell adhesion molecules, including vascular (VCAM), intercellular (ICAM), neural (NCAM) and mucosal addressin (MADCAM) cell adhesion molecules, as well as junction adhesion molecules (JAM). I-set domains are also present in several other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signalling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

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

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

Fibroblast growth factor receptor oncogene partner 2 (FGFR1OP2) was identified in a study on myeloproliferative syndrome (EMS). The study aimed to identify the partner genes to the fibroblast growth factor receptor 1 (FGFR1) involved in the syndrome. Using the 5'-RACE PCR technique, FGFR1OP2 was identified as a novel gene with no known function.

<span class="mw-page-title-main">IL17RD</span>

Interleukin 17 receptor D is a protein that in humans is encoded by the IL17RD gene.

References

  1. ↑ Ornitz DM, Itoh N (2001). "Fibroblast growth factors". Genome Biology. 2 (3): REVIEWS3005. doi: 10.1186/gb-2001-2-3-reviews3005 . PMC   138918 . PMID   11276432.
  2. ↑ Belov AA, Mohammadi M (June 2013). "Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology". Cold Spring Harbor Perspectives in Biology. 5 (6): a015958. doi:10.1101/cshperspect.a015958. PMC   3660835 . PMID   23732477.
  3. 1 2 Duchesne L, Tissot B, Rudd TR, Dell A, Fernig DG (September 2006). "N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding". The Journal of Biological Chemistry. 281 (37): 27178–89. doi: 10.1074/jbc.M601248200 . PMID   16829530.
  4. ↑ Coutts JC, Gallagher JT (December 1995). "Receptors for fibroblast growth factors". Immunology and Cell Biology. 73 (6): 584–9. doi:10.1038/icb.1995.92. PMID   8713482.
  5. ↑ Kalinina J, Dutta K, Ilghari D, Beenken A, Goetz R, Eliseenkova AV, et al. (January 2012). "The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition". Structure. 20 (1): 77–88. doi:10.1016/j.str.2011.10.022. PMC   3378326 . PMID   22244757.
  6. ↑ Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, et al. (June 1996). "Receptor specificity of the fibroblast growth factor family". The Journal of Biological Chemistry. 271 (25): 15292–7. doi: 10.1074/jbc.271.25.15292 . PMID   8663044.
  7. ↑ Davidson D, Blanc A, Filion D, Wang H, Plut P, Pfeffer G, et al. (May 2005). "Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis". The Journal of Biological Chemistry. 280 (21): 20509–15. doi: 10.1074/jbc.M410148200 . PMID   15781473.
  8. ↑ Sleeman M, Fraser J, McDonald M, Yuan S, White D, Grandison P, et al. (June 2001). "Identification of a new fibroblast growth factor receptor, FGFR5". Gene. 271 (2): 171–82. doi:10.1016/S0378-1119(01)00518-2. PMID   11418238.
  9. ↑ Porta R, Borea R, Coelho A, Khan S, Araújo A, Reclusa P, et al. (May 2017). "FGFR a promising druggable target in cancer: Molecular biology and new drugs" (PDF). Critical Reviews in Oncology/Hematology. 113: 256–267. doi:10.1016/j.critrevonc.2017.02.018. hdl: 10447/238074 . PMID   28427515.
  10. 1 2 Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, et al. (February 2017). "Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application". Oncotarget. 8 (9): 16052–16074. doi:10.18632/oncotarget.14109. PMC   5362545 . PMID   28030802.
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