Fibroblast growth factor receptor 2
Encyclopedia
Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 (cluster of differentiation
332) 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 protein encoded by this gene is a member of the fibroblast growth factor receptor
family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin domain
s, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase
domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation
. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte
growth factor, depending on the isoform.
derived tissues and endothelial
organ lining, i.e. skin and internal organs. FGFR2IIIc is found in mesenchyme
, which includes craniofacial
bone and for this reason the mutations of this gene and isoform are associated with craniosynostosis
.
with FGF1
.
The spliced isoforms, however differ in binding:
These differences in binding are not surprising, since FGF ligand is known to bind to the second and third immunoglobulin domain
of the receptor.
family, these receptors signal by binding to their ligand and dimerisation (pairing of receptors), which causes the tyrosine kinase domains to initiate a cascade of intracellular signals. On a molecular level these signals mediate cell division, growth and differentiation.
As mentioned, FGFR2 mutations are associated with craniosynostosis
syndromes, which are skull malformations caused by premature fusion of cranial sutures and other disease features according to the mutation itself. On a molecular level, mutations that affect FGFR2IIIc are associated with marked changes in osteoblast
proliferation and differentiation. Alteration in FGFR2 signalling is thought to underlie the craniosynostosis syndromes. To date, there are two mechanisms of altered FGFR2 signalling. The first is associated with constitutive activation of FGFR, where the FGFR2 receptor is always signalling, regardless of the amount of FGF ligand. This mechanism is found in patients with Crouzon and Pfeiffer syndrome. The second, which is associated with Apert syndrome is a loss of specificity of the FGFR2 isoform, resulting in the receptor binding to FGFs that it does not normally bind.
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
332) is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the FGFR2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor
Fibroblast growth factor
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...
.
The protein encoded by this gene is a member of the fibroblast growth factor receptor
Fibroblast growth factor receptor
The fibroblast growth factor receptors are, as their name implies, receptors that bind to members of the fibroblast growth factor family of proteins. Some of these receptors are involved in pathological conditions...
family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin domain
Immunoglobulin domain
The immunoglobulin domain is a type of protein domain that consists of a 2-layer sandwich of between 7 and 9 antiparallel β-strands arranged in two β-sheets with a Greek key topology....
s, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
growth factor, depending on the isoform.
Isoforms
FGFR2 has two naturally occurring isoforms FGFR2IIIb and FGFR2IIIc, created by splicing of the third immunoglobulin-like domain. FGFR2IIIb is predominantly found in ectodermEctoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
derived tissues and endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
organ lining, i.e. skin and internal organs. FGFR2IIIc is found in mesenchyme
Mesenchyme
Mesenchyme, or mesenchymal connective tissue, is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm, although some are derived from other germ layers; e.g. some mesenchyme is derived from neural crest cells and thus originates from the ectoderm...
, which includes craniofacial
Craniofacial
Craniofacial may be used to describe certain congenital malformations, injuries, surgeons who subspecialize in this area, multi-disciplinary medical-surgical teams that treat and do research on disorders affecting this region, and organizations with interest in...
bone and for this reason the mutations of this gene and isoform are associated with craniosynostosis
Craniosynostosis
Craniosynostosis is a condition in which one or more of the fibrous sutures in an infant skull prematurely fuses by ossification, thereby changing the growth pattern of the skull...
.
Interactions
Fibroblast growth factor receptor 2 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with FGF1
FGF1
Heparin-binding growth factor 1 is a protein that in humans is encoded by the FGF1 gene.-Interactions:FGF1 has been shown to interact with CSNK2B, CSNK2A2, HSPA9, S100A13, Casein kinase 2, alpha 1, Fibroblast growth factor receptor 1, FIBP, Fibroblast growth factor receptor 4, Fibroblast growth...
.
The spliced isoforms, however differ in binding:
- FGFR2IIIb binds to FGF-1FGF1Heparin-binding growth factor 1 is a protein that in humans is encoded by the FGF1 gene.-Interactions:FGF1 has been shown to interact with CSNK2B, CSNK2A2, HSPA9, S100A13, Casein kinase 2, alpha 1, Fibroblast growth factor receptor 1, FIBP, Fibroblast growth factor receptor 4, Fibroblast growth...
, -3FGF3INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the FGF3 gene.- Function :FGF-3 is a member of the fibroblast growth factor family. FGF3 binds to Fibroblast Growth Factor Receptor 3 to serve as a negative regulator of bone growth during ossification...
, -7FGF7Keratinocyte growth factor is a protein that in humans is encoded by the FGF7 gene.-Further reading:...
, -10, -22FGF22Fibroblast growth factor 22 is a protein which in humans is encoded by the FGF22 gene.-Function:The protein encoded by this gene is a member of the fibroblast growth factor family... - FGFR2IIIc binds to FGF-1, -2Basic fibroblast growth factorBasic fibroblast growth factor, also known as bFGF, FGF2 or FGF-β, is a member of the fibroblast growth factor family.- Function :...
, -4FGF4Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.-Further reading:...
, -6FGF6Fibroblast growth factor 6 is a protein that in humans is encoded by the FGF6 gene.-Further reading:...
, -8FGF8Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 gene.-External links:*...
, -9FGF9Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.-Interactions:FGF9 has been shown to interact with Fibroblast growth factor receptor 3.-Further reading:...
, -17FGF17Fibroblast growth factor 17 is a protein that in humans is encoded by the FGF17 gene.-Further reading:...
and -18FGF18Fibroblast growth factor 18 is a protein that in humans is encoded by the FGF18 gene.-Further reading:...
These differences in binding are not surprising, since FGF ligand is known to bind to the second and third immunoglobulin domain
Immunoglobulin domain
The immunoglobulin domain is a type of protein domain that consists of a 2-layer sandwich of between 7 and 9 antiparallel β-strands arranged in two β-sheets with a Greek key topology....
of the receptor.
Clinical significance
Mutations (changes) are associated with numerous medical conditions that include abnormal bone development (e.g. craniosynostosis syndromes) and cancer.Craniosynostosis syndromes
- Apert syndromeApert syndromeApert syndrome is a form of acrocephalosyndactyly, a congenital disorder characterized by malformations of the skull, face, hands and feet. It is classified as a branchial arch syndrome, affecting the first branchial arch, the precursor of the maxilla and mandible...
, the best-known type of acrocephalosyndactyly. This condition is characterized by abnormalities of the skull and face and the hands and feet. - Antley-Bixler syndromeAntley-Bixler syndromeAntley-Bixler syndrome, also called trapezoidocephaly-synostosis syndrome, is a rare, very severe autosomal recessive congenital disorder characterized by malformations and deformities affecting the majority of the skeleton and other areas of the body....
(characterized by trapezoidalTrapezoid boneThe trapezoid bone is a carpal bone in tetrapods, including humans. It is the smallest bone in the distal row. It may be known by its wedge-shaped form, the broad end of the wedge constituting the dorsal, the narrow end the palmar surface; and by its having four articular facets touching each...
, craniofacial and skeletal synostosisSynostosisSynostosis is the abnormal fusion of neighbor bones. It is a type of dysostosis.Examples of synostoses include: craniosynostosis- being an abnormal fusion of two or more cranial bones, radio-ulnar synostosis- being the abnormal fusion of the radius and ulna bones of the forearm, tarsal coalition -...
, plus camptodactylyCamptodactylyCamptodactyly is a medical condition involving fixed flexion deformity of the interphalangeal joints of the little finger. This involves permanent flexure of one or more phalanges...
). Inherited as a recessive trait. - Pfeiffer syndromePfeiffer syndromePfeiffer syndrome is a rare genetic disorder characterized by the premature fusion of certain bones of the skull , which prevents further growth of the skull and affects the shape of the head and face...
(another type of acrocephalosyndactyly). Inherited as a dominant trait, includes broad thumbs and large toes. - Crouzon syndromeCrouzon syndromeCrouzon syndrome is a genetic disorder known as a branchial arch syndrome. Specifically, this syndrome affects the first branchial arch, which is the precursor of the maxilla and mandible...
(a craniofacial disorder with no clinically significant hand or foot problems). Inherited as a dominant trait. - Jackson-Weiss syndromeJackson-Weiss syndromeJackson-Weiss syndrome is a genetic disorder characterized by foot abnormalities and the premature fusion of certain bones of the skull , which prevents further growth of the skull and affects the shape of the head and face...
Cancer
- Breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, a mutation or single nucleotide polymorphismSingle nucleotide polymorphismA single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
(SNP) in intronIntronAn intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
2 of the FGFR2 geneGeneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is associated with a higher breast cancer risk; however the risk is only mildly increased from about 10% lifetime breast cancer risk in the average woman in the industrialized world, to 12-14% risk in carriers of the SNP.
Function and mutations
FGFR2 has important roles in embryonic development and tissue repair, especially bone and blood vessels. Like the other members of the Fibroblast growth factor receptorFibroblast growth factor receptor
The fibroblast growth factor receptors are, as their name implies, receptors that bind to members of the fibroblast growth factor family of proteins. Some of these receptors are involved in pathological conditions...
family, these receptors signal by binding to their ligand and dimerisation (pairing of receptors), which causes the tyrosine kinase domains to initiate a cascade of intracellular signals. On a molecular level these signals mediate cell division, growth and differentiation.
As mentioned, FGFR2 mutations are associated with craniosynostosis
Craniosynostosis
Craniosynostosis is a condition in which one or more of the fibrous sutures in an infant skull prematurely fuses by ossification, thereby changing the growth pattern of the skull...
syndromes, which are skull malformations caused by premature fusion of cranial sutures and other disease features according to the mutation itself. On a molecular level, mutations that affect FGFR2IIIc are associated with marked changes in osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
proliferation and differentiation. Alteration in FGFR2 signalling is thought to underlie the craniosynostosis syndromes. To date, there are two mechanisms of altered FGFR2 signalling. The first is associated with constitutive activation of FGFR, where the FGFR2 receptor is always signalling, regardless of the amount of FGF ligand. This mechanism is found in patients with Crouzon and Pfeiffer syndrome. The second, which is associated with Apert syndrome is a loss of specificity of the FGFR2 isoform, resulting in the receptor binding to FGFs that it does not normally bind.