Article

The Physical Basis of FGFR3 Response to fgf1 and fgf2

Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.
Biochemistry (Impact Factor: 3.02). 09/2011; 50(40):8576-82. DOI: 10.1021/bi200986f
Source: PubMed

ABSTRACT

Fibroblast growth factors (fgfs) play important roles in embryonic development and in adult life by controlling cell proliferation, differentiation, and migration. There are 18 known fgfs which activate four fibroblast growth factor receptors (FGFRs), with different isoforms due to alternative splicing. The physical basis behind the specificity of the biological responses mediated by different fgf-FGFR pairs is currently unknown. To gain insight into the specificity of FGFR3c, a membrane receptor which is critical for bone development, we studied, analyzed, and compared the activation of FGFR3c over a wide range of fgf1 and fgf2 concentrations. We found that while the strength of fgf2 binding to FGFR3c is lower than the strength of fgf1 binding, the fgf2-bound dimers exhibit higher phosphorylation of the critical tyrosines in the activation loop. As a result, fgf1 and fgf2 elicit a similar FGFR3c response at low, but not at high, concentrations. The results demonstrate the versatility of FGFR3c response to fgf1 and fgf2 and highlight the complexity in fgf signaling.

Full-text preview

Available from: ncbi.nlm.nih.gov
  • Source
    • "Blocking antibodies in order to interfere with binding of FGF ligands to FGFR3.Apart from these antibodies are selective for FGFR3 and are activating the CNP-NPR-B-cGMP pathway, which antagonizes MAPK-ERK/p38 signals downstream of FGFR3.Gene Silencing and other genetic therapies. These are used as regulatory RNAs capable of interfering in the protein production, such as micro RNAs (miRNA) or small interfering RNAs (siRNA) [18] [19] [20] [21] [22] [23].This approach is appealing because other natriuretic peptides have been used clinically for their blood effects in adults even in children. Any such treatment would need to be long-termed, starting soon after birth when the diagnosis is made and lasting to puberty [24] [25]. "

    Full-text · Article · Jan 2014
  • Source
    • "After a rinse with ice-cold PBS, the cells were lysed, and the receptors were detected using Western blotting. The cross-linked fraction was calculated as SD/S = SD/(SM+SD), where SD is the intensity of the cross-linked band, and SM is the intensity of the monomeric band [32]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross-linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism.
    Full-text · Article · Apr 2012 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Gly380Arg mutation in FGFR3 is the genetic cause for achondroplasia (ACH), the most common form of human dwarfism. The mutation has been proposed to increase FGFR3 dimerization, but the dimerization propensities of wild-type and mutant FGFR3 have not been compared. Here we use quantitative imaging FRET to characterize the dimerization of wild-type FGFR3 and the ACH mutant in plasma membrane-derived vesicles from HEK293T cells. We demonstrate a small, but statistically significant increase in FGFR3 dimerization due to the ACH mutation. The data are consistent with the idea that the ACH mutation causes a structural change which affects both the stability and the activity of FGFR3 dimers in the absence of ligand.
    Preview · Article · Oct 2012 · PLoS ONE
Show more