The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by the macrophages. They are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in ...

(FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

in FGFR3 can lead to

achondroplasia Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. It is the most common cause of dwarfism and affects about 1 in 27,500 people. In those with the condition, the Rhizomeli ...

Structure

The

receptors consist of an extracellular

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

domain composed of three

immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

-like domains, a single transmembrane

helix A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is for ...

domain, and an

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

domain with

tyrosine kinase 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. Tyrosine kinases belong to a larger cla ...

activity. These receptors bind

s, members of the largest family of growth factor ligands, comprising 22 members. The natural

alternate splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s of FGFR. These isoforms vary in their ligand-binding properties and kinase domains, however all share the common extracellular region composed of three

(Ig)-like domains (D1-D3), and thus belong to the

immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...

. The three immunoglobin(Ig)-like domains—D1, D2, and D3—present a stretch of

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s ("the acid box") between D1 and D2. 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).

FGF7 Keratinocyte growth factor is a protein that in humans is encoded by the ''FGF7'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell sur ...

, however, can only activate FGFR2b, and FGF18 was recently shown to activate FGFR3. 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. The FGFRs are known to dimerize as

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

s and homodimers.

Genes

So far, five distinct membrane FGFR have been identified in

vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

s and all of them belong to the

superfamily (FGFR1 to FGFR4). * (see also

Fibroblast growth factor receptor 1 A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrob ...

) (= CD331) * (see also Fibroblast growth factor receptor 2) (= CD332) * (see also Fibroblast growth factor receptor 3) (= CD333) * (see also Fibroblast growth factor receptor 4) (= CD334) * (see also Fibroblast growth factor receptor-like 1) *

As a drug target

The FGF/FGFR signalling pathway is involved in a variety of cancers. 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. Selective FGFR inhibitors include AZD4547, BGJ398, JNJ42756493, and PD173074.

References

External links

GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes

FGF signaling (with refs)
{{DEFAULTSORT:Fibroblast Growth Factor Receptor Tyrosine kinase receptors