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Identification of Tyrosine Residues in Constitutively Activated Fibroblast Growth Factor Receptor 3 Involved in Mitogenesis, Stat Activation, and Phosphatidylinositol 3-Kinase Activation
- 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.
- Subjects :
- musculoskeletal diseases
STAT3 Transcription Factor
CHO Cells
Protein tyrosine phosphatase
Biology
SH2 domain
Article
Receptor tyrosine kinase
Mice
Phosphatidylinositol 3-Kinases
Cricetinae
Chlorocebus aethiops
Immunoreceptor tyrosine-based activation motif
Animals
Humans
Receptor, Fibroblast Growth Factor, Type 3
Phosphorylation
Molecular Biology
Cell Line, Transformed
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Autophosphorylation
3T3 Cells
Cell Biology
Protein-Tyrosine Kinases
Receptors, Fibroblast Growth Factor
DNA-Binding Proteins
Enzyme Activation
STAT1 Transcription Factor
Biochemistry
COS Cells
ROR1
Trans-Activators
biology.protein
Tyrosine
Mitogen-Activated Protein Kinases
Mitogens
Platelet-derived growth factor receptor
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Subjects
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