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

Oncogene volume 19, pages 3309–3320 (2000)Cite this article

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-γ, 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.

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Acknowledgements

This work was supported by Public Health Service grant NIH/NIDCR RO1 DE12581. We thank Jill Meisenhelder, Pam Maher, and Kari Alitalo for providing reagents, Pedro Ramos and Melanie Webster for assistance in generating constructs, Michael David and Leon Su for advice and discussions regarding Stat experiments, and Laura Castrejon for editorial assistance.

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  1. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, 92093-0367, California, CA, USA

    Kristen C Hart, Scott C Robertson, Martha Y Kanemitsu, April N Meyer, John A Tynan & Daniel J Donoghue

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Hart, K., Robertson, S., Kanemitsu, M. et al. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19, 3309–3320 (2000). https://doi.org/10.1038/sj.onc.1203650

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