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A role for a RhoA/ROCK/LIM-kinase pathway in the regulation of cytotoxic lymphocytes

Z Lou1, D D Billadeau, D N Savoy

  • 1Department of Pharmacology, Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|November 8, 2001
PubMed

Insights

Cytotoxic lymphocytes use a RhoA/ROCK/LIM-kinase pathway to reorganize their actin cytoskeleton. This pathway is crucial for directing lipid rafts and granules for effective cell-mediated killing.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • Cell-mediated killing by cytotoxic lymphocytes requires polarization of lipid rafts and granules.
  • Activation of proximal protein tyrosine kinases is essential for these events.
  • Downstream signaling molecules in this process are not well understood.

Purpose of the Study:

  • To identify downstream intracellular signaling molecules connecting protein tyrosine kinase activation to the actin cytoskeleton reorganization.
  • To elucidate the role of the RhoA/ROCK/LIM-kinase pathway in cytotoxic lymphocyte function.

Main Methods:

  • Pharmacologic inhibition of the RhoA/ROCK/LIM-kinase pathway.
  • Genetic interruption of pathway components.
  • Assessment of F-actin accumulation and lipid raft polarization.
  • Evaluation of cell-mediated cytotoxicity.

Main Results:

  • A RhoA/ROCK/LIM-kinase signaling axis was identified.
  • This pathway links receptor-initiated tyrosine kinase activation to actin cytoskeleton remodeling.
  • Interruption of this pathway blocked F-actin and lipid raft polarization.
  • Inhibition also impaired the delivery of the lethal hit in cytotoxic lymphocytes.

Conclusions:

  • The RhoA/ROCK/LIM-kinase pathway plays a critical role in cytotoxic lymphocyte activation.
  • This pathway is essential for the cytoskeletal reorganization needed for cell-mediated killing.
  • Defines a specialized signaling cascade in immune cell cytotoxic function.

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