Differential Activation of Cysteine-Substitution Mutants of Fibroblast Growth Factor Receptor 3 Is Determined by Cysteine Localization

Adar, R; Monsonego-Ornan, Efrat; David, P.; Yayon, Avner

doi:10.1359/jbmr.2002.17.5.860

Cited by 69 publications

(69 citation statements)

References 32 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experiments using FGFR3 constructs reproducing TD I mutations and Western blot analysis of mutant proteins under non-reducing conditions have convincingly demonstrated the presence of disulphidebonded dimers in transfected cells. 21,22 Based on these data, we assume that formation of a disulphide bond between two mutant receptors would induce constitutive activation of the dimer resulting in ACH or severe HCH phenotypes. Asparagine 262 is conserved between the different members of the FGFR family and is part of a putative glycosylation site N -T -Q.…”

Section: Discussionmentioning

confidence: 99%

Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia

Heuertz

Merrer

Zabel³

et al. 2006

Eur J Hum Genet

View full text Add to dashboard Cite

Achondroplasia (ACH) and hypochondroplasia (HCH) are two autosomal-dominant skeletal disorders caused by recurrent missense FGFR3 mutations in the transmembrane (TM) and tyrosine kinase 1 (TK1) domains of the receptor. Although 98% of ACH cases are accounted for by a single G380R substitution in the TM, a common mutation (N540K) in the TK1 region is detected in only 60-65% of HCH cases. The aim of this study was to determine whether the frequency of mutations in patients with HCH was the result of incomplete mutation screening or genetic heterogeneity. Eighteen exons of the FGFR3 gene were entirely sequenced in a cohort of 25 HCH and one ACH patients in whom common mutations had been excluded. Seven novel missense FGFR3 mutations were identified, one causing ACH and six resulting in HCH. Six of these substitutions were located in the extracellular region and four of them creating additional cysteine residues, were associated with severe phenotypes. No mutations were detected in 19 clinically diagnosed HCH patients. Our results demonstrate that the spectrum of FGFR3 mutations causing short-limb dwarfism is wider than originally recognised and emphasise the requirement for complete screening of the FGFR3 gene if appropriate genetic counselling is to be offered to patients with HCH or ACH lacking the most common mutations and their families.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia

Heuertz

Merrer

Zabel³

et al. 2006

Eur J Hum Genet

View full text Add to dashboard Cite

show abstract

“…cDNA encoding human FGFR2␤ (IIIc) was cut out from pBluescript (RZPD, Clone ID: IMAGp998N0911701Q3) with NotI and SpeI and ligated into pcDNA3. The pcDNA3-hFGFR3 (IIIc) construct was a generous gift from Dr Avner Yayon, ProChon Biotech, Israel (Adar et al, 2002). Hybrid and deleted mutants of the FGFRs as described below, were made using combinations of standard techniques such as PCR, a Quick change site-directed mutagenesis kit (Stratagene) and subclonings.…”

Section: Methodsmentioning

confidence: 99%

Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor C-terminal tail

Sørensen¹,

Wiedlocha²,

Haugsten³

et al. 2006

Journal of Cell Science

View full text Add to dashboard Cite

Members of the fibroblast growth factor family bind to one or more of the four closely related membrane-spanning FGF receptors. In addition to signaling through the receptors, exogenous FGF-1 and FGF-2 are endocytosed and translocated to the cytosol and nucleus where they stimulate RNA and DNA synthesis. Here we have studied the ability of the four FGF receptors to facilitate translocation of exogenous FGF-1 to the cytosol and nucleus. FGFR1 and FGFR4 were able to mediate translocation, whereas FGFR2 and FGFR3 completely lacked this ability. By analyzing mutant FGFRs we found that the tyrosine kinase domain could be deleted from FGFR1 without abolishing translocation, whereas the Cterminal tail of the FGFRs, constituted by approximately 50 amino acids downstream of the kinase domain, plays a crucial role in FGF-1 translocation. Three amino acids residues within the C-terminal tail were found to be of particular importance for translocation. For FGFR2, the two amino acid substitutions Q774M and P800H were sufficient to enable the receptor to support FGF-1 translocation. The results demonstrate a striking diversity in function of the four FGFRs determined by their Cterminal domain.

show abstract

“…The extracellular missense substitutions most often give rise to an unpaired cysteine, leading to ligand-independent dimerization of FGFR3. These mutations cause markedly different levels of constitutive FGFR3 activation, possibly owing to a differential impact on the orientation of the cytoplasmic kinase domain (30,31). The most frequent mutations are S249C, Y375C, R248C, G372C, and K652E, which together account for 98% of all FGFR3 mutations in bladder cancer (32).…”

Section: Inducible Shrna Knockdown Of Fgfr3 Attenuates Bladder Cancermentioning

confidence: 99%

Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

Jiang¹,

Du²,

Chen³

et al. 2009

J. Clin. Invest.

224

210

View full text Add to dashboard Cite

show abstract

Differential Activation of Cysteine-Substitution Mutants of Fibroblast Growth Factor Receptor 3 Is Determined by Cysteine Localization

Cited by 69 publications

References 32 publications

Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia

Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia

Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor C-terminal tail

Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

Contact Info

Product

Resources

About