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PMID:10918587

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Citation

Hart, KC, Robertson, SC, Kanemitsu, MY, Meyer, AN, Tynan, JA and Donoghue, DJ (2000) Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19:3309-20

Abstract

The fibroblast growth factor receptor (FGFR) family members mediate a number of important cellular processes, and are mutated or overexpressed in several forms of human cancer. Mutation of Lys650-->Glu in the activation loop of the FGFR3 kinase domain causes the lethal human skeletal disorder thanatophoric dysplasia type II (TDII) and is also found in patients with multiple myeloma, bladder and cervical carcinomas. This mutation leads to constitutive activation of FGFR3. To compare the signaling activity of FGFR family members, this activating mutation was generated in FGFR1, FGFR3, and FGFR4. We show that the kinase domains of FGFR1, FGFR3, and FGFR4 containing the activation loop mutation, when targeted to the plasma membrane by a myristylation signal, can transform NIH3T3 cells and induce neurite outgrowth in PC12 cells. Phosphorylation of Shp2, PLC-gamma, and MAPK was also stimulated by all three 'TDII-like' FGFR derivatives. Additionally, activation of Stat1 and Stat3 was observed in cells expressing the activated FGFR derivatives. Finally, we demonstrate that FGFR1, FGFR3, and FGFR4 derivatives can stimulate PI-3 kinase activity. Our comparison of these activated receptor derivatives reveals a significant overlap in the panel of effector proteins used to mediate downstream signals. This also represents the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation. Moreover, our results suggest that Stat activation by FGFRs is important in their ability to act as oncogenes.

Links

PubMed Online version:10.1038/sj.onc.1203650

Keywords

3T3 Cells; Amino Acid Sequence; Animals; Cell Division; Cell Line, Transformed; Cell Transformation, Neoplastic; DNA-Binding Proteins/metabolism; Enzyme Activation; Humans; Intracellular Signaling Peptides and Proteins; Isoenzymes/metabolism; Mice; Mitogen-Activated Protein Kinases/metabolism; Molecular Sequence Data; Myristic Acid; PC12 Cells; Phosphatidylinositol 3-Kinases/metabolism; Phospholipase C gamma; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases/metabolism; Protein-Tyrosine Kinases; Rats; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 3; Receptor, Fibroblast Growth Factor, Type 4; Receptors, Fibroblast Growth Factor/genetics; Receptors, Fibroblast Growth Factor/metabolism; STAT1 Transcription Factor; STAT3 Transcription Factor; Trans-Activators/metabolism; Type C Phospholipases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FGFR1

located_in

GO:0005887: integral component of plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FGFR4

located_in

GO:0005887: integral component of plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FGFR4

involved_in

GO:0008543: fibroblast growth factor receptor signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FGFR4

enables

GO:0005007: fibroblast growth factor-activated receptor activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FGFR3

involved_in

GO:0000165: MAPK cascade

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FGFR3

located_in

GO:0005887: integral component of plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FGFR3

involved_in

GO:0008543: fibroblast growth factor receptor signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FGFR3

part_of

GO:0005887: integral component of plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FGFR3

enables

GO:0005007: fibroblast growth factor-activated receptor activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FGFR1

part_of

GO:0005887: integral component of plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete


See also

References

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