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Development of an In Vitro Assay to Evaluate Contractile Function of Mesenchymal Cells that Underwent Epithelial-Mesenchymal Transition
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Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal

Wa Xian1, Kathryn L Schwertfeger, Jeffrey M Rosen

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

Molecular Endocrinology (Baltimore, Md.)
|February 8, 2007
PubMed

Insights

Fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have distinct roles in cancer. Signaling duration, not receptor type, dictates outcomes like cell survival or apoptosis in epithelial cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Receptor tyrosine kinases (RTKs), including fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2), play critical roles in cell signaling.
  • These homologous RTKs exhibit distinct functions during carcinogenesis, necessitating a deeper understanding of their specific signaling pathways.
  • Investigating RTK signaling in polarized epithelial cells is crucial for understanding tissue homeostasis and disease development.

Purpose of the Study:

  • To investigate the distinct signaling mechanisms of FGFR1 and FGFR2 in polarized epithelial cells.
  • To elucidate how the duration of downstream signaling influences cellular phenotypes mediated by homologous RTKs.
  • To establish a model system for studying RTK signaling in a three-dimensional (3D) epithelial context.

Main Methods:

  • Development of an in vitro 3D HC11 mouse mammary epithelial cell culture model.
  • Utilized a chemically inducible FGFR (iFGFR) dimerization system to activate FGFR1 and FGFR2.
  • Assessed cell proliferation, polarity, survival, apoptosis, and epithelial-to-mesenchymal transition (EMT).
  • Investigated downstream signaling kinetics, receptor down-regulation, and the role of the proteasome pathway.

Main Results:

  • Both iFGFR1 and iFGFR2 activation initiated cell proliferation and loss of polarity.
  • Only iFGFR1 activation promoted cell survival and epithelial-to-mesenchymal transition (EMT).
  • iFGFR2 activation induced apoptosis and rapid receptor down-regulation with transient downstream signaling.
  • Inhibition of proteasome activity in iFGFR2-activated cells rescued EMT and promoted invasive phenotypes.
  • The duration of downstream signaling, influenced by proteasomal degradation, determined distinct cellular responses.

Conclusions:

  • The duration of downstream signaling is a critical determinant of distinct cellular phenotypes mediated by homologous RTKs.
  • FGFR1 and FGFR2 signaling can be differentiated by their impact on cell survival, apoptosis, and EMT.
  • Proteasome-mediated regulation of signaling duration plays a key role in controlling RTK-driven cellular plasticity and invasive potential.

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