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This version published online on February 6, 2007
Molecular Endocrinology, doi:10.1210/me.2006-0518
A more recent version of this article appeared on April 1, 2007
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Submitted on December 4, 2006
Accepted on January 31, 2007

Distinct roles of FGFR1 and FGFR2 in regulating cell survival and epithelial-mesenchymal transition

Wa Xian, Kathryn L. Schwertfeger, and Jeffrey M. Rosen*

Department of Molecular and Cellular Biology (W.X., J.M.R.), Baylor College of Medicine, Houston, TX 77030; and Department of Lab Medicine and Pathology (K.L.S.), University of Minnesota Cancer Center, Minneapolis, MN 55455

* To whom correspondence should be addressed. E-mail: jrosen{at}faculty.bcm.tmc.edu.

Two related receptor tyrosine kinases (RTKs), fibroblast growth factor receptor 1 and 2 (FGFR1 and FGFR2) exert distinct effects during carcinogenesis. To examine FGFR1 and FGFR2 signaling in polarized epithelia, we have developed an in vitro three-dimensional (3D) HC11 mouse mammary epithelial cell culture model combined with a chemically inducible FGFR (iFGFR) dimerization system. While activation of both RTKs led to reinitiation of cell proliferation and loss of cell polarity, only iFGFR1 activation induced cell survival and epithelial to mesenchymal transition (EMT). In contrast, iFGFR2 activation induced cell apoptosis even in the cells in direct contact with the extracellular matrix. Activation of iFGFR2, but not iFGFR1, led to rapid receptor down-regulation and transient activation of downstream signaling, which were partially rescued by Cbl siRNA knockdown or the proteasome inhibitor, lactacystin. Importantly, inhibition of proteasome activity in iFGFR2-activated structures led to EMT and invasive phenotypes resembling those observed following iFGFR1 activation. These studies demonstrate, for the first time, that the duration of downstream signaling determines the distinct phenotypes mediated by very homologous RTKs in 3D cultures.
Key words: breast cancer • 3D culture • FGFR1 • FGFR2 • inducible dimerization




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