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cAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge

Karen S Lyle1, Judith H Raaijmakers, Wytse Bruinsma

  • 1Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.

Cellular Signalling
|March 19, 2008
PubMed

Insights

The small GTPase Rap inhibits epithelial cell migration by slowing focal adhesion dynamics and leading edge protrusion. This finding reveals a novel role for Rap in regulating cell motility beyond integrin affinity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Epithelial cell migration is vital for development, wound healing, and metastasis.
  • This process relies on cell-cell adhesion, integrin-ECM interactions, and actomyosin-driven protrusion.
  • The small GTPase Rap is known to regulate integrins and cadherins, but its direct role in cell migration was unexplored.

Purpose of the Study:

  • To investigate the direct role of the small GTPase Rap in epithelial cell migration.
  • To determine how Rap activation affects key migration processes like focal adhesion dynamics and leading edge protrusion.

Main Methods:

  • Activation of endogenous Rap using cyclic AMP (cAMP).
  • Assessment of epithelial cell migration induced by HGF and TGF-beta in various model systems.
  • Analysis of focal adhesion dynamics and membrane protrusion using microscopy.
  • Short-term cell adhesion assays and antibody-mediated integrin activation.

Main Results:

  • cAMP-induced Rap activation inhibited HGF- and TGF-beta-induced epithelial cell migration.
  • Rap activation slowed focal adhesion dynamics and inhibited polarized membrane protrusion.
  • Forced integrin activation did not replicate Rap's inhibitory effects on cell motility, despite mimicking short-term adhesion effects.

Conclusions:

  • Rap activation inhibits epithelial cell migration by modulating focal adhesion dynamics and leading edge activity.
  • This function of Rap extends beyond integrin affinity modulation.
  • Rap plays an additional role in controlling the machinery of epithelial cell migration.

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