FGFR2 gene

The FGFR2 gene (FGFR2 stands for: Fibroblast Growth Factor Receptor 2) is a protein-coding gene. GO (Gene Ontology) annotations associated with this gene include protein homodimerization activity and protein kinase activity. An important paralog of this gene is FGFR1. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

The FGFR proteins encoded by this gene and its isoforms are involved in a variety of signaling pathways that are known to play an important role in cancer. Activation of these receptors can lead to activation of the RAS-MAPK signaling pathway and the PI3K-AKT signaling pathway, among others. The mechanisms by which FGFR can be dysregulated vary depending on the type of cancer. Amplification of receptors has been observed in lung and breast cancer, coding mutations and deletions have been observed in many cancers, and more recently, FGFR fusions leading to pathway activation have been shown to have oncogenic potential in several cancer types. The targeted therapeutics ponatinib, dovitinib and pazopanib have proven successful in treating overactive FGFR signaling, leading to the use of diagnostic sequencing targeting the FGFR genes, particularly in lung cancer patients.

The protein encoded by this gene belongs to the family of fibroblast growth factor receptors, in which the amino acid sequence is highly conserved between members and over the course of evolution. Members of the FGFR family differ from each other in their ligand affinity and tissue distribution. A representative full-length protein consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular part of the protein interacts with fibroblast growth factors and initiates a cascade of downstream signaling that ultimately influences mitogenesis and differentiation.

The protein encoded by this gene is the "Keratinocyte Growth Factor Receptor", a high-affinity receptor for acidic, basic and/or keratinocyte growth factors. Depending on the mutated isoform in this gene, associations with:

Crouzon syndrome (The activated FGFs/FGFR2 signaling disrupts the balance between differentiation, cell proliferation and apoptosis via its downstream signaling pathways. However, very little is known about the cellular and molecular factors that lead to the severity of this phenotype. Uncovering the molecular pathology of craniosynostosis will be of great value for genetic counseling, diagnosis, prognosis and early intervention programs Al-Namnam NM et al. 2019).

• Pfeiffer syndrome
• craniosynostosis
• Apert syndrome
• Jackson-Weiss syndrome
• Beare-Stevenson-Cutis-Gyrata syndrome
• Saethre-Chotzen syndrome
• syndromic craniosynostosis

syndromic craniosynostosis.

Tyrosine protein kinase that acts as a cell surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis as well as in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of differentiation, proliferation and apoptosis of osteoblasts and is required for normal skeletal development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to activation of multiple signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol-1,4,5-trisphosphate. Phosphorylation of FRS2 triggers the recruitment of GRB2, GAB1, PIK3R1 and SOS1 and mediates the activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway as well as the AKT1 signaling pathway. FGFR2 signaling is downregulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation result in defective signaling. Overexpressed FGFR2 promotes the activation of STAT1.

1. Al-Namnam NM et al (2019) Crouzon syndrome: Genetic and intervention review. J Oral Biol Craniofac Res 9:37-39.
2. Jahan N et al. (2023) Evaluation of the Association between FGFR2 Gene Polymorphisms and Breast Cancer Risk in the Bangladeshi Population. Genes (Basel) 14:819.
3. Minashi K et al. (2021) Cancer-related FGFR2 overexpression and gene amplification in Japanese patients with gastric cancer. Jpn J Clin Oncol 51:1523-1533.