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Vol. 12, Issue 4, 931-942, April 2001
Department of Chemistry and Biochemistry, and Center for Molecular
Genetics, University of California, San Diego, La Jolla, California
92093-0367
Fibroblast growth factor receptor 3 (FGFR3) mutations are
frequently involved in human developmental disorders and cancer. Activation of FGFR3, through mutation or ligand stimulation, results in
autophosphorylation of multiple tyrosine residues within the intracellular domain. To assess the importance of the six conserved tyrosine residues within the intracellular domain of FGFR3 for signaling, derivatives were constructed containing an N-terminal myristylation signal for plasma membrane localization and a point mutation (K650E) that confers constitutive kinase activation. A
derivative containing all conserved tyrosine residues stimulates cellular transformation and activation of several FGFR3 signaling pathways. Substitution of all nonactivation loop tyrosine residues with
phenylalanine rendered this FGFR3 construct inactive, despite the
presence of the activating K650E mutation. Addition of a single tyrosine residue, Y724, restored its ability to stimulate cellular transformation, phosphatidylinositol 3-kinase activation, and phosphorylation of Shp2, MAPK, Stat1, and Stat3. These results demonstrate a critical role for Y724 in the activation of multiple signaling pathways by constitutively activated mutants of FGFR3.
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