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Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell

E di Martino1, C G L'Hôte, W Kennedy

  • 1Cancer Research UK Clinical Centre, Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.

Oncogene
|September 15, 2009
PubMed

Insights

Activating fibroblast growth factor receptor 3 (FGFR3) mutations in urothelial cells promote proliferation by overcoming cell density limits. These effects are specific to both the cell type and the particular FGFR3 mutation.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Activating fibroblast growth factor receptor 3 (FGFR3) mutations are common in bladder cancer.
  • Limited information exists on the specific effects of these mutations in urothelial cells.

Purpose of the Study:

  • To investigate the cell-type and mutation-specific phenotypic and signaling consequences of FGFR3 mutations in human urothelial cells and mouse fibroblasts.
  • To understand the basis for the observed mutation spectrum in FGFR3.

Main Methods:

  • Utilized immortalized normal human urothelial cells (TERT-NHUC) and mouse fibroblasts (NIH-3T3).
  • Introduced three specific FGFR3 mutations (S249C, Y375C, K652E) into these cell lines.
  • Analyzed downstream signaling pathways including FRS2alpha, ERK1/2, AKT, SRC, and PLCgamma1 phosphorylation.
  • Assessed cellular phenotypes such as proliferation, viability, saturation density, and anchorage-independent growth.

Main Results:

  • In urothelial cells, FGFR3 mutations activated FRS2alpha and ERK1/2 signaling.
  • Common mutations (S249C, Y375C) induced PLCgamma1 phosphorylation, increased proliferation, and viability, overcoming contact inhibition.
  • The rare K652E mutation did not phosphorylate PLCgamma1 and lacked these phenotypic effects.
  • In fibroblasts, all FGFR3 mutations activated Src, Akt, and PLCgamma1, leading to transformation, proliferation, and anchorage-independent growth.

Conclusions:

  • The functional consequences of FGFR3 mutations are highly specific to both the cell type and the particular mutation.
  • Mutant FGFR3 may provide a selective advantage in the urothelium by enabling cells to evade normal proliferation controls.
  • Understanding these specific effects is crucial for targeted bladder cancer therapies.

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