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FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

Wenchao Zhou1, Xiujing Feng, Yingjie Wu

  • 1State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Graduate University of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.

Cell Research
|August 5, 2009
PubMed

Insights

Fibroblast growth factor receptor substrate 2alpha (FRS2alpha) integrates signals. A negative regulatory loop involving MAPK and FRS2 acts as a molecular switch, controlling cell differentiation signals.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Fibroblast growth factor (FGF) receptor substrate 2alpha (FRS2alpha) is a key mediator in FGF signaling.
  • Mitogen-activated protein kinase (MAPK) negatively regulates FGF signaling by phosphorylating FRS2.
  • FRS2 phosphorylation suggests a role in crosstalk between growth factor signaling pathways.

Purpose of the Study:

  • To investigate the inhibitory effect of EGF co-stimulation on FGF-induced FRS2 phosphorylation.
  • To identify the mechanism by which MAPK signaling affects FRS2 phosphorylation.
  • To explore the functional consequences of FRS2 phosphorylation on cell differentiation.

Main Methods:

  • Utilized PC12 cells for experiments involving FGF and EGF stimulation.
  • Employed U0126, a MEK inhibitor, to assess the role of MAPK pathway.
  • Generated and analyzed a FRS2 mutant (FRS2-3KL) lacking MAPK binding and phosphorylation sites.

Main Results:

  • EGF co-stimulation attenuated FGF-induced FRS2 phosphorylation in PC12 cells, an effect reversed by U0126.
  • Identified an ERK1/2-binding motif in FRS2 and created the FRS2-3KL mutant.
  • FRS2-3KL cells showed enhanced differentiation potential compared to WT FRS2 cells upon FGF treatment, and EGF could not inhibit FGF-induced FRS2-3KL phosphorylation.

Conclusions:

  • The FRS2-MAPK pathway acts as a negative regulatory loop, functioning as a molecular switch.
  • This switch integrates inhibitory signals from other pathways into FGFR signaling.
  • Modulation of FRS2 phosphorylation impacts cell differentiation potential.

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