Disease relevance of FGFR2

• All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome [1].
• Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1-3) [1].
• In addition, a recently identified ligand-dependent S252L/A315S double mutation in FGFR2 was shown to cause syndactyly in the absence of craniosynostosis [2].
• Pfeiffer syndrome (PS) is one of the classical craniosynostosis syndromes correlated with specific mutations in the human fibroblast growth factor receptor (FGFR) genes, FGFR1 and FGFR2 [3].
• Expression of FGFR1 and FGFR2 in prostate cancer (CaP) was not found to be associated with clinical parameters [4].

High impact information on FGFR2

• Interestingly, this common mutation occurs precisely at the analogous position within the FGFR3 protein as the mutations in FGFR1 (Pro252Arg) and FGFR2 (Pro253Arg) previously reported in Pfeiffer and Apert syndromes, respectively [5].
• Apert syndrome results from one or other of two specific nucleotide substitutions, both C-->G transversions, in the fibroblast growth factor receptor 2 (FGFR2) gene [6].
• The gene on chromosome 10 is FGFR2 with several different mutations causing sporadic and familial PS (Table 1) [5].
• FGFR2 mutations in Pfeiffer syndrome [7].
• Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes [8].

Chemical compound and disease context of FGFR2

• We therefore conclude that aberrant expression of alternatively spliced isoforms of FGFR2 with the C3 carboxyl terminus in the SUM-52 breast cancer cells results in sustained activation of signal transduction leading to transformation [9].
• This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal [10].
• K-SAM/FGFR2 gene encodes a receptor tyrosine kinase which belongs to the fibroblast growth factor receptor family and is amplified and overexpressed in KATO-III gastric cancer cells [11].
• A Novel Molecular Targeting Compound as K-samII/FGF-R2 Phosphorylation Inhibitor, Ki23057, for Scirrhous Gastric Cancer [12].
• In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues [13].

Biological context of FGFR2

• Although the majority (61/62 in the cohort sample) of FGFR2 mutations localized to the IIIa and IIIc exons, we identified mutations in seven additional exons-including six distinct mutations of the tyrosine kinase region and a single mutation of the IgII domain [14].
• It has been known for several years that heterozygous mutations of three members of the fibroblast growth-factor-receptor family of signal-transduction molecules-namely, FGFR1, FGFR2, and FGFR3-contribute significantly to disorders of bone patterning and growth [14].
• Gain-of-function missense mutations in FGF receptor 2 (FGFR2) are responsible for a variety of craniosynostosis syndromes including Apert syndrome (AS), Pfeiffer syndrome (PS) and Crouzon syndrome (CS) [2].
• A variety of human skeletal dysplasias have been linked to specific point mutations in FGFR1, FGFR2 and FGFR3 leading to severe impairment in cranial, digital and skeletal development [15].
• For FGFR2, the two amino acid substitutions Q774M and P800H were sufficient to enable the receptor to support FGF-1 translocation [16].

Anatomical context of FGFR2

• Furthermore, the expression of the high-affinity receptor tyrosine kinase to KGF (FGFR2) is predominantly detectable in alpha2beta1(hi) CD133- TAP cells when compared with stem cells (alpha2beta1(hi) CD133+), which would therefore be relatively unresponsive to the differentiating effect of KGF [17].
• Thus, by mimicking the paracrine pathway (on proliferation, growth in soft agar and invasion) on the human prostatic epithelial cell line PNT1A positively checked for FGFR2/IIIb expression, FGF7 significantly enhanced cell proliferation at an optimal concentration of 7.5 x 10(-11) M, but no significant invasion or growth in soft agar were observed [18].
• In an in vitro control model of calvarial osteoblasts from Apert patients carrying the FGFR2 P253R mutation, we studied the changes in cellular phenotype and evaluated the effects of FGF2 [19].
• Reverse transcription-polymerase chain reaction and Southern blot transfer of mRNA derived from 7 SCCHN cell lines showed that the IIIb isoform of FGF-receptor 2 (FGFR2) was expressed at high levels, whereas the IIIc isoform and FGFRI were weakly expressed or not detected [20].
• Widespread co-expression of FGFR1 and FGFR2 was observed in intimal smooth muscle cells, foam cells and the plaque microvasculature of simple and advanced lesions [21].

Associations of FGFR2 with chemical compounds

• Here we report the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide [22].
• Mutations in FGFR2 clustered at two critical cysteine residues, 278 and 342, which were involved in 18 of 30 cases (60%) [23].
• H16N2 cells expressing the full-length FGFR2 with the C1 or C3 carboxyl terminus were tested for their ability to grow under epidermal growth factor (EGF)-independent conditions, in soft agar, and for their ability to invade naturally occurring basement membranes and compared with the parental SUM-52PE cell line [24].
• Phosphorylation of the adapter protein FGF receptor substrate 2 is much more robust in the cells expressing the C3 variant of FGFR2 compared with the C1 variant [24].
• These PCSCs possessed estrogen receptors and KGFR, but not androgen receptor as determined by RT-PCR and Western blot, respectively [25].

Physical interactions of FGFR2

• Within the FGFR family, Pyk2 also interacted significantly with FGFR2 [26].
• EMSA analysis of mutant osteoblast nuclear extracts showed reduced Runx2 binding to a target OSE2 site in the Fgfr2 promoter [27].
• Here we demonstrate using a cell free system that, at low concentrations of heparin, FGF4 binds only to FGFR-2, while much higher heparin levels are required for binding to FGFR-1 [28].

Co-localisations of FGFR2

• Cytokeratin 20 (CK 20) colocalized with KGFR [29].

Regulatory relationships of FGFR2

• FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b) [30].
• FGF-R1 was expressed in all samples and FGF-R2 in most [31].
• CONCLUSIONS: KGF and KGFR expression was upregulated in ADPKD kidney tissues [32].
• Cbl-mediated ubiquitination of alpha5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation [33].
• This provides genetic and biochemical evidence for a role of Fgfr2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the SCS [27].

Other interactions of FGFR2

• We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2 [34].
• By prior convention, the previously reported from of FGFR3 was designated IIIc due to its high degree of homology with the IIIc domain of FGFR1 (83% homology) and the IIIc domain of FGFR2 (81% homology) [35].
• FGFR1, FGFR2 and FGFR4 were expressed at high levels in respectively 22%, 4% and 32% of tumors [36].
• The sequence variations c.590C>G and c.582-62G>A in FGF8, and, c.550+27C>T, c.727+180T>G, c.830T>C (p.Me186Thr), and c.2454C>T in FGFR2 were found uniquely in patients with hypospadias, as compared with 96 controls [37].
• During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts [38].
• Reexpression of FGFR2 competes with FGFR1 for the immediate substrate FGFR substrate 2 to impede signaling upstream of the BRAF/MAPK pathway [39].

Analytical, diagnostic and therapeutic context of FGFR2

• Here, we analyze the effect of the canonical AS mutations, the D321A PS mutation and the S252L/A315S double mutation on FGFR2 ligand binding affinity and specificity using surface plasmon resonance [2].
• METHODS: The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH [40].
• METHODS: The expression of bFGF, fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor 2 (FGFR2) was analyzed by immunohistochemistry and Western blot [41].
• The expression of FGFR1 and of the Bek and KGFR isoforms of FGFR2 has, therefore, been studied in human hand development at 12 weeks by in situ hybridization [42].
• To understand the mechanism by which KGF exerts protective functions on epithelial cells, we used the yeast two-hybrid assay to identify proteins that interact with the KGF receptor (KGFR) [43].

References