Back to Search Start Over

Identification of Tyrosine Residues in Constitutively Activated Fibroblast Growth Factor Receptor 3 Involved in Mitogenesis, Stat Activation, and Phosphatidylinositol 3-Kinase Activation

Authors :
Kristen C. Hart
Scott C Robertson
Daniel J. Donoghue
Source :
Molecular Biology of the Cell. 12:931-942
Publication Year :
2001
Publisher :
American Society for Cell Biology (ASCB), 2001.

Abstract

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.

Details

ISSN :
19394586 and 10591524
Volume :
12
Database :
OpenAIRE
Journal :
Molecular Biology of the Cell
Accession number :
edsair.doi.dedup.....5333e055970fb79011ac2297186da032
Full Text :
https://doi.org/10.1091/mbc.12.4.931