Autocatalytic phosphorylation of FGFR3 point mutants with enhanced kinase activity

Stable Identifier
R-HSA-2033485
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Activated point mutants in the transmembrane and kinase domains of FGFR3 have been shown to undergo constitutive autophosphorylation in a ligand-independent manner (Naski, 1996; Webster, 1996 and Donoghue, 1996; Webster, 1996; Bellus, 2000; Goriely, 2009). Some of the point mutants, including K650E and G380R, may also be able to further respond after exposure to ligand (Naski, 1996). Dimerization and activation of the FGFR3 transmembrane mutants is thought to occur via the formation of non-native hydrogen bonds that promote intermolecular interactions (Webster and Donoghue 1996), while the kinase domain mutants activate phosphorylation by mimicking conformational changes in the activation loop (Webster, 1996). Mutants with enhanced kinase activity appear to be activated to differing extents that, for the most part, correlate with the severity of the disease phenotype (Webster, 1996; Bellus, 2000; Goriely, 2009), although the results of in vitro kinase assays with immunoprecipitated proteins do not fully recapitulate the pathological consequences of the mutation (Goriely, 2009). K650E has also been shown to transform NIH 3T3 cells (Chesi, 2001).

Literature References
PubMed ID Title Journal Year
8754806 Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II

Webster, MK, d'Avis, PY, Robertson, SC, Donoghue, DJ

Mol Cell Biol 1996
8640234 Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia

Naski, MC, Wang, Q, Xu, J, Ornitz, DM

Nat Genet 1996
19855393 Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

Goriely, A, Hansen, RM, Taylor, IB, Olesen, IA, Jacobsen, GK, McGowan, SJ, Pfeifer, SP, McVean, GA, Rajpert-De Meyts, E, Wilkie, AO

Nat Genet 2009
8599935 Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia

Webster, MK, Donoghue, DJ

EMBO J 1996
11157491 Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma

Chesi, M, Brents, LA, Ely, SA, Bais, C, Robbiani, DF, Mesri, EA, Kuehl, WM, Bergsagel, PL

Blood 2001
11055896 Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype

Bellus, GA, Spector, EB, Speiser, PW, Weaver, CA, Garber, AT, Bryke, CR, Israel, J, Rosengren, SS, Webster, MK, Donoghue, DJ, Francomano, CA

Am J Hum Genet 2000
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
protein tyrosine kinase activity of FGFR3 point mutant dimers with enhanced kinase activity [plasma membrane]
Physical Entity
Activity
Disease
Name Identifier Synonyms
bone development disease 0080006
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created
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