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p27Kip1 modulates cell migration through the regulation of RhoA activation

Arnaud Besson1, Mark Gurian-West, Anja Schmidt

  • 1Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Division of Basic Science, Seattle, WA 98109, USA.

Genes & Development
|April 14, 2004
PubMed

Insights

The tumor suppressor p27, also known as p27(Kip1), regulates cell migration independently of its cell cycle functions. It inhibits the Rho pathway by binding to RhoA, thereby controlling cell motility.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The tumor suppressor p27(Kip1) is a known inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes, crucial for cell cycle regulation.
  • p27(Kip1) also possesses cell cycle-independent functions that are increasingly being recognized.

Purpose of the Study:

  • To investigate the role of p27(Kip1) in cell migration.
  • To elucidate the mechanism by which p27(Kip1) regulates cell motility, independent of its cell cycle functions.

Main Methods:

  • Comparison of cell migration and motility in p27(Kip1)-null fibroblasts versus wild-type cells.
  • Assessment of actin stress fibers, focal adhesions, and RhoA pathway activation.
  • Analysis of p27(Kip1) binding to RhoA and its effect on RhoA activation by guanine-nucleotide exchange factors (GEFs).

Main Results:

  • p27(Kip1)-null fibroblasts showed significantly reduced motility compared to wild-type cells.
  • Loss of p27(Kip1) led to increased actin stress fibers and focal adhesions, indicative of Rho pathway activation.
  • Active RhoA levels were elevated in p27(Kip1)-null cells, and ROCK inhibition rescued migration defects.
  • p27(Kip1) directly binds to RhoA, inhibiting its activation by GEFs.

Conclusions:

  • p27(Kip1) plays a novel, cell cycle-independent role in regulating cell migration.
  • This regulation is mediated through the modulation of the Rho pathway, specifically by inhibiting RhoA activation.
  • Understanding this mechanism opens new avenues for targeting cell migration in various biological contexts.

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