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Cooperativity between the Ras-ERK and Rho-Rho kinase pathways in urokinase-type plasminogen activator-stimulated cell

Minji Jo1, Keena S Thomas, Avril V Somlyo

  • 1Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

The Journal of Biological Chemistry
|January 24, 2002
PubMed

Insights

Urokinase-type plasminogen activator (uPA) and ERK signaling pathways cooperate to drive cancer cell migration. Blocking either the ERK or Rho-Rho kinase pathway inhibits migration, revealing a crucial interplay in cell movement.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Signaling

Background:

  • Urokinase-type plasminogen activator (uPA) binding to its receptor initiates cell signaling pathways.
  • The integration of these signals to alter cell physiology is not fully understood.
  • ERK and Rho-Rho kinase pathways are implicated in cell migration.

Purpose of the Study:

  • To investigate the interplay between ERK and Rho-Rho kinase pathways in cell migration.
  • To determine how uPA-mediated signaling influences these pathways.
  • To elucidate the mechanisms by which cell migration is regulated.

Main Methods:

  • Utilized MCF-7 breast cancer and HT-1080 fibrosarcoma cell lines.
  • Stimulated cell migration using uPA, epidermal growth factor, and constitutively active MEK1.
  • Employed MEK-specific antagonist PD098059 and Rho-Rho kinase pathway antagonists (Y-27632, dominant-negative RhoA).
  • Assessed ERK phosphorylation and GTP-bound RhoA levels.

Main Results:

  • ERK activation by uPA, EGF, or MEK1 stimulated cell migration.
  • MEK and Rho-Rho kinase pathway antagonists blocked ERK-stimulated migration.
  • uPA did not significantly increase RhoA activity, suggesting constitutive Rho pathway activity supports ERK-driven migration.
  • Antagonizing Rho kinase paradoxically increased ERK phosphorylation but did not promote migration.
  • ERK-independent migration was not inhibited by Rho kinase antagonists.

Conclusions:

  • The Ras-ERK and Rho-Rho kinase pathways cooperate to promote cell migration.
  • Neutralizing either pathway is sufficient to block migration stimulated by ERK activation.
  • This cooperative model provides insight into the regulation of cell motility in cancer.

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