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

Polarization of lipid rafts and granules to the site of target contact is r equired for the development of cell-mediated killing by cytotoxic lymphocyt es. We have previously shown that these events require the activation of pr oximal protein tyrosine kinases. However, the downstream intracellular sign aling molecules involved in the development of cell-mediated cytotoxicity r emain poorly defined. We report here that a RhoA/ROCK/LIM-kinase axis coupl es the receptor-initiated protein tyrosine kinase activation to the reorgan ization of the actin cytoskeleton required for the polarization of lipid ra fts and the subsequent generation of cell-mediated cytotoxicity. Pharmacolo gic and genetic interruption of any element of this RhoA/ROCK/LIM-kinase pa thway inhibits both the accumulation of F-actin and lipid raft polarization to the site of target contact and the subsequent delivery of the lethal hi t. These data define a specialized role for a RhoA --> ROCK --> LIM-kinase pathway in cytotoxic lymphocyte activation.