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FGFR3

Official Full Name
fibroblast growth factor receptor 3
Organism
Homo sapiens
GeneID
2261
Background
This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, 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 binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]
Synonyms
ACH; CEK2; JTK4; CD333; HSFGFR3EX;
Bio Chemical Class
Kinase
Protein Sequence
MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRSPPKKGLGSPTVHKISRFPLKRQVSLESNASMSSNTPLVRIARLSSGEGPTLANVSELELPADPKWELSRARLTLGKPLGEGCFGQVVMAEAIGIDKDRAAKPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIINLLGACTQGGPLYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQVARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKKTTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCTHDLYMIMRECWHAAPSQRPTFKQLVEDLDRVLTVTSTDEYLDLSAPFEQYSPGGQDTPSSSSSGDDSVFAHDLLPPAPPSSGGSRT
Open
Disease
Alzheimer disease, Bladder cancer, Breast cancer, Coronary atherosclerosis, Endometrial cancer, Liver cancer, Multiple myeloma, Myeloproliferative neoplasm, Myocardial infarction, Renal cell carcinoma, Retina cancer, Skeletal anomaly, Solid tumour/cancer, Ureteral cancer
Approved Drug
1 +
Clinical Trial Drug
11 +
Discontinued Drug
1 +

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Detailed Information

Fibroblast growth factor receptor 3 (FGFR3) is a crucial gene located on human chromosome 4p16.3, encoding a receptor protein that plays a significant role in the regulation of cell growth, differentiation, and bone development. FGFR3, a member of the fibroblast growth factor receptor (FGFR), family, has a substantially conserved amino acid sequence with other family members. Usually including three main regions—an external domain made of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and an intracellular tyrosine kinase domain—fgFRs are tyrosine kinase receptors. FGFR3 binds to fibroblast growth factors (FGFs), then sets off a sequence of intracellular signaling events impacting cellular functions vital for maintenance and development.

Because it controls chondrocyte differentiation and endochondral ossification—the process by which bone arises from cartilage—fgFR3 is highly important for bone development. Through its activity, FGFR3 regulates skeletal development during childhood; mutations in this gene are associated with several skeletal diseases including achondroplasia, hypochondroplasia, and craniosynostosis. Many times, these mutations cause aberrant receptor activation or reduced receptor maturation, therefore upsetting the signaling and causing skeletal abnormalities.

Figure 1 illustrates the FGFR signaling pathway, highlighting the binding of FGFs to FGFR extracellular domains, which triggers receptor dimerization, activation of downstream signaling cascades such as RAS-MAPK and PI3K-AKT, and the negative regulation of this pathway by various modulators like CBL, SPRY, SEF, and Dusp-6.Figure 1. FGFR signaling pathway (Ascione CM, et al., 2023)

FGFR3 Mutations and Their Impact on Skeletal Disorders

Several forms of skeletal dysplasia, the most prevalent of which is achondroplasia, a disorder causing dwarfism, have their main genetic cause found to be the FGFR3 gene. Because their cartilage development in long bones stops early, those with achondroplasia have small stature, especially in the limbs. This is directly the outcome of mutations in FGFR3 that make it constitutively active, so stopping the appropriate development of bone and blocking the expansion of cartilage. Though it causes low stature, another related condition called hypochondroplasia also comes from mutations in FGFR3 and has less severe bone growth problems than achondroplasia.

Beyond these well-known skeletal disorders, mutations in FGFR3 have been linked to a variety of other diseases, including craniosynostosis, a disorder in which the sutures of the skull fuse early to produce an aberrant head shape and possible developmental abnormalities. Usually including alterations in the extracellular domain or intracellular signaling areas, these mutations compromise normal receptor performance. Fascinating studies have revealed that not all mutations in FGFR3 cause skeletal dysplasia; some can be connected to other forms of developmental abnormalities or cancers including bladder and nasopharyngeal tumors.

FGFR3 in Cancer

The function of FGFR3 goes beyond only bone growth; its dysregulation has major consequences for cancer biology, especially in malignancies where FGFR3 mutations or amplifications are prevalent. Many bladder malignancies show genetic changes in the FGFR3 gene. All of these changes—point mutations, gene amplifications, and gene rearrangements—help to activate downstream signaling pathways including PLCγ, PI3K-AKT, and RAS-MAPK. Key aspects of malignant development, these pathways encourage angiogenesis, survival, and unchecked cell proliferation.

The frequent mutations in the tumor suppressor genes TP53 and RB1 in bladder cancer point to the early occurrence of FGFR3 alterations in carcinogenesis. Studies have revealed that almost half of bladder cancer cases had mutations in the FGFR3 coding sequence; rearranging FGFR3 is especially prevalent. Especially, these mutations are predictive biomarkers for patient responses to medicines aiming at FGFR targets.

Apart from bladder cancer, various additional malignancies like nasopharyngeal carcinoma and glioblastoma have been shown to have FGFR3 mutations, where their influence on oncogenesis is a subject of active study. Consequently, especially in malignancies displaying abnormal FGFR signaling, FGFR3 is being more and more seen as a target for therapeutic intervention.

Pathways of FGFR3 Signaling

Like other members of the FGFR family, FGFR3 turns on multiple intracellular signaling cascades upon ligand binding. Involved in cell development, differentiation, and survival, the RAS-MAPK and PI3K-AKT pathways rank among the most important of these. The receptor dimerizes upon FGFR3 activation, a process that brings its intracellular tyrosine kinase domains close together so they may phosphorize one another. This phosphorylation event activates downstream signaling proteins, including FRS2α (fibroblast growth factor receptor substrate 2 alpha), which is essential for recruiting additional adaptors like GRB2, GAB1, and SOS1, so inducing additional signaling via the RAS-MAPK and PI3K-AKT pathways.

Furthermore, PLCγ's activation produces crucial secondary messengers including inositol triphosphate (IP3) and diacylglycerol (DAG), which control calcium release from the endoplasmic reticulum and activate protein kinase C (PKC), so contributing to different physiological responses. Moreover, the STAT signaling pathway—which involves the activation of STAT1 and STAT3—also controls immunological responses and cell survival quite critically.

Although normal cellular activities depend on these signaling pathways, their dysregulation in FGFR3 can cause uncontrolled cell proliferation, survival, and invasion—qualities of cancer. For some tumors, especially those with overexpressed or mutant versions of the receptor, this makes FGFR3 a powerful oncogene.

Therapeutic Aspects and Future Directions

Finding FGFR3 as both a major oncogene and a fundamental regulator in skeletal development has provided fresh treatment approaches. Particularly in tumors where FGFR3 mutations or amplitudes are common, the development of FGFR3 inhibitors shows great promise for study. Targeted medications such as ponatinib, dovitinib, and pazopanib have shown promise in reducing FGFR3 activity, providing hope for those with cancers that have evolved resistance to traditional therapy.

Apart from cancer treatment, continuous study on the possibilities of FGFR3-targeted treatments for skeletal diseases including achondroplasia is under progress. While mutations driving these disorders typically cause FGFR3 to be constitutively active, current research indicates that altering FGFR3 signaling may offer a therapeutic method to fix growth anomalies.

Understanding the intricate regulatory mechanisms controlling FGFR3 activity and how its malfunction contributes to disease will help to shape FGFR3 research going forward. The field of FGFR3-related treatments will continue to be shaped by additional research on the creation of specific FGFR3 inhibitors and their possible uses in both cancer and skeletal diseases.

References:

  1. Ascione CM, Napolitano F, et al. Role of FGFR3 in bladder cancer: Treatment landscape and future challenges. Cancer Treat Rev. 2023 Apr;115:102530.
  2. Laederich MB, Horton WA. FGFR3 targeting strategies for achondroplasia. Expert Rev Mol Med. 2012 Jan 19;14:e11.
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