Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia.

Abstract

Achondroplasia, the most common genetic form of dwarfism, is an autosomal dominant disorder whose underlying mechanism is a defect in the maturation of the cartilage growth plate of long bones. Achondroplasia has recently been shown to result from a Gly to Arg substitution in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3), although the molecular consequences of this mutation have not been investigated. By substituting the transmembrane domain of the Neu receptor tyrosine kinase with the transmembrane domains of wild‐type and mutant FGFR3, the Arg380 mutation in FGFR3 is shown to activate both the kinase and transforming activities of this chimeric receptor. Residues with side chains capable of participating in hydrogen bond formation, including Glu, Asp, and to a lesser extent, Gln, His and Lys, were able to substitute for the activating Arg380 mutation. The Arg380 point mutation also causes ligand‐independent stimulation of the tyrosine kinase activity of FGFR3 itself, and greatly increased constitutive levels of phosphotyrosine on the receptor. These results suggest that the molecular basis of achondroplasia is unregulated signal transduction through FGFR3, which may result in inappropriate cartilage growth plate differentiation and thus abnormal long bone development. Achondroplasia may be one of the number of cogenital disorders where constitutive activation of a member of the FGFR family leads to development abnormalities.

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

“…The role of FGF-2 in cartilage has been most studied in the growth plate, where it has an inhibitory effect on chondrocyte proliferation. Gain-of-function mutations in human FGF receptor 3 (FGFR-3) (23)(24)(25)(26)(27) and overexpression of FGF-2 (28) or intravenous treatment of mice with recombinant FGF-2 (29) all result in a reduction in the proliferating zone of the growth plate and in subsequent shortening of the long bones (achondroplastic dwarfism). The absence of a developmental phenotype in Fgf2 -/-mice is thought to be due to compensation by other FGF family members such as FGF-18 which are present in the growth plate (30).…”

Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis

“…The FGFR4 Gly388Arg polymorphism results in an amino-acid change in the transmembrane domain, which is a highly conserved region for receptor tyrosine kinase. Analogous missense mutations in the transmembrane domain in the FGFR3 gene, resulting from a Gly to Arg substitution at codon 380, were proposed to result in constitutive activation of FGFR3 signaling (Webster and Donoghue, 1996). In general, activating FGFR3 mutations are associated with favourable disease characteristics such as low stage and grade, low recurrence rate, and a lower mortality rate (Sibley et al, 2001;van Rhijn et al, 2001).…”

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…This mutation activates FGFR3 in the absence of ligand. However, the mutant receptor is further activated in the presence of ligand (Naski et al 1996;Webster and Donoghue 1996;Li et al 1997). Two different substitution mutations account for most cases of TD.…”

“…However, the majority of craniosynostosis syndromes are associated with mutations in Fgfr2 ( Fig. 2; Muenke and Schell 1995;Park et al 1995;Malcolm and Reardon 1996;Webster and Donoghue 1997;Wilkie 1997;Burke et al 1998;Lajeunie et al 1999;Ornitz 2001). The pathophysiology and genetics of craniosynostosis syndromes have been recently reviewed (Wilkie 1997(Wilkie , 2000Cohen 2000b;Britto et al 2001a;Wilkie and Morriss-Kay 2001).…”