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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent

Yongyou Zhang1, Yongshun Lin, Courtney Bowles

  • 1Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A & M University System Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030-3303, USA.

The Journal of Biological Chemistry
|October 30, 2004
PubMed

Insights

Fibroblast growth factors (FGFs) activate cell cycle progression by a novel pathway. FGFs release Cks1 from FRS2, promoting p27(Kip1) degradation and cyclin-dependent kinase activation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Fibroblast growth factors (FGFs) are potent mitogens activating signaling pathways.
  • The precise mechanisms by which FGF receptor (FGFR) tyrosine kinases induce cell cycle progression and antiapoptotic activity are not fully elucidated.
  • The role of the mitogen-activated protein kinase (MAPK) pathway in mediating all FGF effects remains under investigation.

Purpose of the Study:

  • To investigate a novel signaling pathway downstream of FGFR tyrosine kinases.
  • To determine if the MAPK pathway solely mediates FGF-induced cell cycle progression.
  • To elucidate the interaction between FGFR substrate 2 (FRS2), Cks1, and p27(Kip1) in response to FGF stimulation.

Main Methods:

  • Co-immunoprecipitation assays to study protein-protein interactions.
  • Western blotting to detect protein phosphorylation and degradation.
  • Cell cycle analysis in 3T3 cells stimulated with FGF.

Main Results:

  • Cell cycle inducer Cks1 associates with the unphosphorylated form of FGFR substrate 2 (FRS2).
  • FGF stimulation leads to FGFR activation, FRS2 phosphorylation, and subsequent release of Cks1 from FRS2.
  • Degradation of p27(Kip1) is promoted, facilitating the activation of cyclin E/A-Cdk complexes and G(1)/S phase transition.

Conclusions:

  • A novel FGF-mediated signaling pathway involves the direct activation of cyclin-dependent kinases.
  • This pathway bypasses sole reliance on the MAPK cascade for cell cycle induction.
  • FRS2 acts as a crucial adaptor protein linking FGFR activation to cell cycle machinery via Cks1 and p27(Kip1).

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