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p38MAPK induces cell surface alpha4 integrin downregulation to facilitate erbB-2-mediated invasion

Kathleen M Woods Ignatoski1, Navdeep K Grewal, Sonja Markwart

  • 1Department of Radiation Oncology and the Comprehensive Cancer Center, University of Michigan Health Systems, Ann Arbor, MI 48109-0948, USA.

Neoplasia (New York, N.Y.)
|March 28, 2003
PubMed

Insights

Overexpressing erbB-2 in mammary cells causes invasiveness by downregulating alpha(4) integrin. This process involves Rac 1 and p38MAPK signaling pathways, highlighting their role in cell transformation and metastasis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Overexpression of erbB-2 in breast cancer cells leads to growth factor independence and transformed phenotypes.
  • Understanding the mechanisms of erbB-2-mediated transformation is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of erbB-2 in inducing cell invasiveness and alpha(4) integrin downregulation in human mammary epithelial (HME) cells.
  • To elucidate the signaling pathways, specifically involving small G-proteins like Rac 1 and p38MAPK, that mediate these erbB-2-induced effects.

Main Methods:

  • Overexpression of erbB-2 in HME cells.
  • Utilizing dominant-negative and constitutively active forms of Rac 1.
  • Employing a p38MAPK inhibitor to assess its impact on invasiveness and alpha(4) integrin levels.
  • Quantifying cell surface alpha(4) integrin expression and cell invasiveness.

Main Results:

  • ErbB-2 overexpression in HME cells resulted in alpha(4) integrin downregulation and increased invasiveness.
  • Rac 1 activation was essential for erbB-2-mediated invasion and alpha(4) integrin downregulation.
  • Inhibition of p38MAPK blocked invasiveness and reversed alpha(4) integrin downregulation in erbB-2-overexpressing cells.

Conclusions:

  • ErbB-2 signaling activates Rac 1, which subsequently activates p38MAPK, leading to alpha(4) integrin downregulation.
  • Downregulation of alpha(4) integrin contributes to erbB-2-mediated cell invasiveness.
  • This study provides a mechanistic link between erbB-2, Rac 1, p38MAPK, and alpha(4) integrin in promoting cell transformation and invasion.

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