Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4

The fibroblast growth factor receptor (FC;FR) family members mediate a numb er of important cellular processes, and are mutated or overexpressed in sev eral forms of human cancer. Mutation of Lys650 --> Glu in the activation lo op of the FGFR3 kinase domain causes the lethal human skeletal disorder tha natophoric dysplasia type II (TDII) and is also found in patients with mult iple myeloma, bladder and cervical carcinomas. This mutation leads to const itutive activation of FGFR3, To compare the signaling activity of FGFR fami ly members, this activating mutation aas generated in FGFR1, FGFR3, and FGF R I. We show that the kinase domains of FGFR1, FGFR3, and FGFR3 containing the activation loop mutation, when targeted to the plasma membrane by a myr istylation signal, can transform NIH3T3 cells and induce neurite outgrowth in PC12 cells. Phosphorylation of Shp2, PLC-gamma, and MAPK was also stimul ated by all three 'TDII-like' FGFR derivatives. Additionally, activation of Stat1 and Stat3 mas observed in cells expressing the activated FGFR deriVa tives. 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 protein s used to mediate downstream signals. This also represents the first demons tration that activation of FGFR3, in addition to FGFR1 and FGFR3, can induc e cellular transformation. Moreover, our results suggest that Stat activati on by FGFRs is important in their ability to act as oncogenes.