Fibroblast growth factor receptor 1
|Fibroblast growth factor receptor 1|
|Symbols||; BFGFR; CD331; CEK; FGFBR; FGFR-1; FLG; FLT-2; FLT2; HBGFR; HH2; HRTFDS; KAL2; N-SAM; OGD; bFGF-R-1|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
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.
The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) 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-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 both acidic and basic fibroblast growth factors and is involved in limb induction.
Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, Trigonocephaly, osteoglophonic dysplasia, squamous cell lung cancer (14) and autosomal dominant Kallmann syndrome. There is also strong evidence from sequencing studies of candidate genes involved in clefting that mutations in the FGFR1 gene may be associated in the pathogenesis of cleft lip and/or palate. A few DNA sequence variants, including one nonsense mutation, have been reported in isolated or non-syndromic cleft lip and palate. Both cleft lip with or without a cleft palate and cleft palate only features have been seen in families with a FGFRI mutation. Cleft palate is a relatively common feature of Kallman syndrome as well. Somatic chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.
Mutations in in this gene have been associated to .
Somatic mutations of FGFR1 occurs in several diseases including breast and lung cancers. FGFR1 has an amplification of 9%–15% in breast cancer. Its amplified expression is generally associated with poor prognosis and relapse. In ER+ breast cancer, its amplification is associated with aggressive metastasis. Its also associated as a cancer subtype as amplification of it and ERBB2 is mutually exclusive. Apart from gene amplification, a somatic mutation called K566R has also been associated with basal-like triple negative breast cancer.
Amplification of FGFR1 is also a feature in 20% of lung cancer patients. FGFR1 amplification was a single largest prognostic factor in a cohort of SCCL patients and associated with smoking. It has also been detected amplified in NSCLC cancer patients. Chromosomal translocations are an important factor in FGFR1's involvement in cancer. FGFR1 fusions have been detected with BCR and ZFN198, indicating interactions with conventional oncogenic pathways. There fusion proteins can transform cells and induce SCLL cancer in mice. Multiple myelomas also harbor a t(4;14) translocation of the FGFR1 gene. The translocation brings FGFR in proximity to the IgH enchancer region leading to overexpression. In prostrate cancer, expression of FGFR1 leads to an induced EMT of cancer cells. This mechanism probably involves interaction with stromal cancer associated fibroblasts leading to dynamics that stimulates NFkB and as a result cell invasiveness.
The mechanism of FGFR1 action on cancer is largely based on abetting cancer progression and metastasis. Fibroblast growth factors trigger the autophosphorylation of the receptors at important tyrosine residues within activation locus of the tyrosine kinase domain. This autophosphorylation results in change of the structural conformation of the tyrosine kinase domain from an inactive form to an active one  This activated tyrosine kinase domain downstream phosphorylates other tyrosine residues on their substrate-binding sites along with FGFR-bound adaptor molecules in a stepwise manner through a process of phosphotase transferase. This phosphorylation of the tyrosine residue at the C-terminal region of receptor allows for the binding site of phospholipase Cγ in recruiting and activating PLCγ for the catalysis and transformation of phosphatidylinositol diphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3). FGF signals are downstream effected into the RAS-MAPK or PI3K-AKT signaling cascades. SRC tyrosine kinase are also activated by FGF signals. FGFR1 receives fibroblast binding proteins and concurrently activates both the Ras-MAPK/ERK and the PI3K pathway. Both these pathways are fundamentally important to cancer cells as they provide signals to proliferate and survive respectively. As the control of these pathways is tuned by the presence of the FGF receptor, ordinarily it would not be an issue in epithelial cells. However cancer cells that undergo EMT take up a more messenchymal state. In these cases the FGF receptors are upregulated leading to a greater tendency to move to the messenchymal state and increased aggressiveness as well as motility.
FGFR1 activity also displays focal dependence in terms of ligand signaling. Basal FGFR1 signaling was lower in FGFR1 inhibitor sensitive cell lines such as DMS114. However on addition of FGFs, the p-ERK pathway was highly stimulated. Under steady state conditions the cell lines exhibited high levels of FGF secretion and under serum starvation conditions the cells still produced above average levels of FGF. This indicates that even under nutrition deficient conditions, FGF secretion and presence of FGFRs on cell surface allow cells to sustain growth. Interestingly, pERK could be activated by FGF1 but FGFR levels were unaffected by the presence of FGF inhibitor. This results to the conclusion that a certain baseline level of FGF activity possibly through autocrine or paracrine signaling sustains the display of FGF receptors even in conditions that normally would not favor growth. Its this counterintuitive presence of receptor that allows cancer cells to grow in a non-growth environment.
Recent advances in our knowledge of the FGFR1 system has resulted in attempts to discover therapeutic touch points in the pathway for use in drug development. FGFR-targeted drugs exert direct as well as indirect anticancer effects, because FGFRs on cancer cells and endothelial cells are involved in tumorigenesis and vasculogenesis, respectively. FGFR therapeutics are active as FGF affects numerous morphologies of cancers such as invasiveness, stemness and cellular survival. Primary among such drugs are antagonists. Small molecules that fit between the ATP binding pockets of the tyrosine kinase domains of the receptors. For FGFR1 numerous such small molecules are already approved for targeting of the structure of TKI ATP pocket. These include Dovitinib and Brivanib. The table below provides the IC50 (Nanomolar) of Small-Molecule Compounds Targeting FGFRs.
FGFR1 aberration in breast and lung cancer as a result of genetic overamplification is effectively targeted using Dovitinib and Povatinib respectively. Drug resistance is a a highly relevant avant fore topic in the field of drug development for FGFR targets. FGFR inhibitors allow for the increase of tumor sensitivity to regular anticancer drug such as paclitaxel, and etoposide in human cancer cells and thereby enhancing antiapoptotic potential based on aberrant FGFR activation. Moreover, FGF signaling inhibition dramatically reduces revascularization, hitting upon one of the hallmarks of cancers, angiogenesis, and reduces tumor burden in human tumors that depend on autocrine FGF signaling based on FGF2 upregulation following the common VEGFR-2 therapy for breast cancer. In such a way, FGFR1 can act synergistically with therapies to cut off cancer clonal resurgence by eliminating potential pathways of future relapse. In addition, FGFR inhibitors are predicted to be effective on relapsed tumors because of the clonal evolution of an FGFR-activated minor subpopulation after therapy targeted to EGFRs or VEGFRs. Because there are multiple mechanisms of action for FGFR inhibitors to overcome drug resistance in human cancer, FGFR-targeted therapy is a promising strategy for the treatment of refractory cancer.
Fibroblast growth factor receptor 1 has been shown to interact with:
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- EntrezGene 2260
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- GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes
- GeneReviews/NCBI/NIH/UW entry on Kallmann syndrome
- FGFR1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Fibroblast growth factor receptor 1 on the Atlas of Genetics and Oncology
- FGFR1 human gene location in the UCSC Genome Browser.
- FGFR1 human gene details in the UCSC Genome Browser.