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Selective desensitization of growth factor signaling by cell adhesion to fibronectin

Niki C Galownia1, Keiichiro Kushiro, Yuan Gong

  • 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

The Journal of Biological Chemistry
|June 2, 2007
PubMed

Insights

Cell adhesion enhances growth factor (GF)-mediated signaling, but this effect is not universal. Adhesion can unexpectedly desensitize cells to certain GFs, depending on dose and timing.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Extracellular Matrix Interactions

Background:

  • Cell adhesion to the extracellular matrix is crucial for growth factor (GF)-mediated cellular functions like proliferation.
  • Adhesion is known to enhance GF-induced intracellular signals, particularly the Ras-extracellular signal-regulated kinase (Erk) pathway.
  • The universality of adhesion-mediated enhancement across different GFs remains unclear due to diverse Ras-Erk activation mechanisms.

Purpose of the Study:

  • To investigate whether adhesion-mediated enhancement of Erk signaling is a universal phenomenon across different growth factors.
  • To quantify the dynamics of Erk signaling in response to epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) under varying adhesion conditions.
  • To elucidate the specific conditions and mechanisms underlying adhesion's influence on GF signaling.

Main Methods:

  • Utilized NIH-3T3 fibroblasts cultured on fibronectin-coated surfaces.
  • Quantified the dynamics of Erk signaling activation induced by EGF, bFGF, and PDGF.
  • Manipulated the timing and dose of GF stimulation in conjunction with cell adhesion to assess signaling responses.

Main Results:

  • Adhesion enhanced Erk signaling for EGF but not for bFGF or PDGF.
  • Unexpectedly, cell adhesion desensitized Erk signaling at subsaturating doses of bFGF and PDGF, rendering cells unresponsive to GF.
  • Adhesion-mediated desensitization occurred rapidly and was influenced by the timing of GF exposure; concurrent GF and adhesion stimulation partially rescued the desensitization.

Conclusions:

  • Adhesion-dependent enhancement of Erk signaling is not universal and is specific to certain growth factors like EGF.
  • Cell adhesion can actively desensitize cells to other GFs (bFGF, PDGF) in a dose- and time-dependent manner.
  • The desensitization mechanism likely targets a regulatory point upstream of Ras, close to GF receptor activation, highlighting the complex interplay between adhesion and signaling.

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