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PKB mediates c-erbB2-induced epithelial beta1 integrin conformational inactivation through Rho-independent F-actin

Shahram Hedjazifar1, Lachmi E Jenndahl, Hiroaki Shimokawa

  • 1Department of Medical Biochemistry, University of Göteborg, Box 440, SE-405 30 Göteborg, Sweden.

Experimental Cell Research
|June 1, 2005
PubMed

Insights

Proto-oncogene c-erbB2 signaling inhibits cell adhesion by altering integrin conformation via MEK1/2 and PKB pathways. This involves actin depolymerization and Rho GTPase activation, impacting cell matrix interactions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Proto-oncogene c-erbB2 signaling inhibits integrin alpha(2)beta(1) adhesive function in mammary epithelial cells.
  • This inhibition is mediated by MAP ERK kinase 1/2 (MEK1/2) and protein kinase B (PKB) pathways.

Purpose of the Study:

  • To elucidate the mechanisms by which c-erbB2 signaling suppresses matrix adhesion.
  • To investigate the role of integrin conformation, actin cytoskeleton, and Rho GTPase in this process.

Main Methods:

  • Analysis of integrin alpha(2)beta(1) conformation and function in human mammary epithelial cells.
  • Investigation of the involvement of MEK1/2, PKB, and Rho GTPase signaling pathways.
  • Assessment of actin depolymerization and stress fiber formation.

Main Results:

  • c-erbB2 signaling induces an inactive conformation of the beta(1) integrin subunit via MEK1/2 and PKB.
  • Actin depolymerization is essential for this conformational switch.
  • Rho GTPase is activated by c-erbB2 and is necessary for integrin inactivation and delayed stress fiber reformation.

Conclusions:

  • Oncogenic growth factor signaling inhibits matrix adhesion through multiple pathways converging on integrin conformation.
  • PKB mediates initial actin depolymerization and its effects on integrin function.
  • Rho signaling influences integrin activation independently of the cytoskeleton.

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