This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Webster, M. K.
Right arrow Articles by Donoghue, D. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Webster, M. K.
Right arrow Articles by Donoghue, D. J.

 Previous Article  |  Next Article 

Mol. Cell. Biol., 10 1997, 5739-5747, Vol 17, No. 10
Copyright © 1997, American Society for Microbiology

Enhanced signaling and morphological transformation by a membrane- localized derivative of the fibroblast growth factor receptor 3 kinase domain

MK Webster and DJ Donoghue
Department of Chemistry and Biochemistry and Center for Molecular Genetics, University of California, San Diego, La Jolla 92093-0367, USA.

Fibroblast growth factor (FGF) receptors (FGFRs) are membrane-spanning tyrosine kinase receptors that mediate regulatory signals for cell proliferation and differentiation in response to FGFs. We have previously determined that the Lys650-->Glu mutation in the activation loop of the kinase domain of FGFR3, which is responsible for the lethal skeletal dysplasia thanatophoric dyplasia type II (TDII), greatly enhances the ligand-independent kinase activity of the receptor. Here, we demonstrate that expression of this construct induces a c-fos promoter construct approximately 10-fold but does not lead to proliferation or morphological transformation of NIH 3T3 cells. In contrast, the isolated kinase domain of activated FGFR3, targeted to the plasma membrane by a myristylation signal, is able to stimulate c- fos expression by 40-fold, induce proliferation of quiescent cells, and morphologically transform fibroblasts. This result suggests that the extracellular and transmembrane domains of FGFRs exert a negative regulatory influence on the activity of the kinase domain. Targeting of the activated kinase domain to either the cytoplasm or the nucleus does not significantly affect biological signaling, suggesting that signals from FGFR3 resulting in mitogenesis originate exclusively from the plasma membrane. Furthermore, our novel observation that expression of a highly activated FGFR3 kinase domain is able to morphologically transform fibroblasts suggests that dysregulation of FGFR3 has the potential to play a role in human neoplasia.


This article has been cited by other articles:

  • Meyer, A. N., McAndrew, C. W., Donoghue, D. J. (2008). Nordihydroguaiaretic Acid Inhibits an Activated Fibroblast Growth Factor Receptor 3 Mutant and Blocks Downstream Signaling in Multiple Myeloma Cells. Cancer Res. 68: 7362-7370 [Abstract] [Full Text]  
  • Nakazawa, F., Nagai, H., Shin, M., Sheng, G. (2006). Negative regulation of primitive hematopoiesis by the FGF signaling pathway. Blood 108: 3335-3343 [Abstract] [Full Text]  
  • Nowroozi, N., Raffioni, S., Wang, T., Apostol, B. L., Bradshaw, R. A., Thompson, L. M. (2005). Sustained ERK1/2 but not STAT1 or 3 activation is required for thanatophoric dysplasia phenotypes in PC12 cells. Hum Mol Genet 14: 1529-1538 [Abstract] [Full Text]  
  • Meyer, A. N., Gastwirt, R. F., Schlaepfer, D. D., Donoghue, D. J. (2004). The Cytoplasmic Tyrosine Kinase Pyk2 as a Novel Effector of Fibroblast Growth Factor Receptor 3 Activation. J. Biol. Chem. 279: 28450-28457 [Abstract] [Full Text]  
  • Bakkar, A. A., Wallerand, H., Radvanyi, F., Lahaye, J.-B., Pissard, S., Lecerf, L., Kouyoumdjian, J. C., Abbou, C. C., Pairon, J.-C., Jaurand, M.-C., Thiery, J.-P., Chopin, D. K., Gil Diez de Medina, S. (2003). FGFR3 and TP53 Gene Mutations Define Two Distinct Pathways in Urothelial Cell Carcinoma of the Bladder. Cancer Res. 63: 8108-8112 [Abstract] [Full Text]  
  • van Rhijn, B. W.G., Vis, A. N., van der Kwast, T. H., Kirkels, W. J., Radvanyi, F., Ooms, E. C.M., Chopin, D. K., Boeve, E. R., Jobsis, A. C., Zwarthoff, E. C. (2003). Molecular Grading of Urothelial Cell Carcinoma With Fibroblast Growth Factor Receptor 3 and MIB-1 is Superior to Pathologic Grade for the Prediction of Clinical Outcome. JCO 21: 1912-1921 [Abstract] [Full Text]  
  • Wang, Q., Green, R. P., Zhao, G., Ornitz, D. M. (2001). Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development 128: 3867-3876 [Abstract] [Full Text]  
  • Hart, K. C., Robertson, S. C., Donoghue, D. J. (2001). Identification of Tyrosine Residues in Constitutively Activated Fibroblast Growth Factor Receptor 3 Involved in Mitogenesis, Stat Activation, and Phosphatidylinositol 3-Kinase Activation. Mol. Biol. Cell 12: 931-942 [Abstract] [Full Text]  
  • van Rhijn, B. W. G., Lurkin, I., Radvanyi, F., Kirkels, W. J., van der Kwast, T. H., Zwarthoff, E. C. (2001). The Fibroblast Growth Factor Receptor 3 (FGFR3) Mutation Is a Strong Indicator of Superficial Bladder Cancer with Low Recurrence Rate. Cancer Res. 61: 1265-1268 [Abstract] [Full Text]  
  • Chesi, M., Brents, L. A., Ely, S. A., Bais, C., Robbiani, D. F., Mesri, E. A., Kuehl, W. M., Bergsagel, P. L. (2001). Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97: 729-736 [Abstract] [Full Text]  
  • Sandberg, M. L., Kaykas, A., Sugden, B. (2000). Latent Membrane Protein 1 of Epstein-Barr Virus Inhibits as Well as Stimulates Gene Expression. J. Virol. 74: 9755-9761 [Abstract] [Full Text]  
  • Keresztes, M., Boonstra, J. (1999). Import(ance) of Growth Factors in(to) the Nucleus. JCB 145: 421-424 [Full Text]  
  • Yap, A. S., Niessen, C. M., Gumbiner, B. M. (1998). The Juxtamembrane Region of the Cadherin Cytoplasmic Tail Supports Lateral Clustering, Adhesive Strengthening, and Interaction with p120ctn. JCB 141: 779-789 [Abstract] [Full Text]  
  • Shimizu, A., Tada, K., Shukunami, C., Hiraki, Y., Kurokawa, T., Magane, N., Kurokawa-Seo, M. (2001). A Novel Alternatively Spliced Fibroblast Growth Factor Receptor 3 Isoform Lacking the Acid Box Domain Is Expressed during Chondrogenic Differentiation of ATDC5 Cells. J. Biol. Chem. 276: 11031-11040 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»