A Role for a RhoA/ROCK/LIM-Kinase Pathway in the Regulation of Cytotoxic Lymphocytes

• Published in: The Journal of immunology (1950) 2001-11, Vol.167 (10), p.5749-5757
• Main Authors: Lou, Zhenkun, Billadeau, Daniel D, Savoy, Doris N, Schoon, Renee A, Leibson, Paul J
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Amides - pharmacology; Animals; Cell Adhesion; Cell Polarity; Cells, Cultured; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Enzyme Inhibitors - pharmacology; Humans; Intracellular Signaling Peptides and Proteins; LIM kinase; Lim Kinases; Lymphocyte Activation; Membrane Microdomains - ultrastructure; Mice; Mutation; Protein Kinase Inhibitors; Protein Kinases - genetics; Protein Kinases - physiology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; Pyridines - pharmacology; rho-Associated Kinases; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - physiology; RhoA protein; ROCK protein; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - ultrastructure; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.10.5749

Polarization of lipid rafts and granules to the site of target contact is required for the development of cell-mediated killing by cytotoxic lymphocytes. We have previously shown that these events require the activation of proximal protein tyrosine kinases. However, the downstream intracellular signaling molecules involved in the development of cell-mediated cytotoxicity remain poorly defined. We report here that a RhoA/ROCK/LIM-kinase axis couples the receptor-initiated protein tyrosine kinase activation to the reorganization of the actin cytoskeleton required for the polarization of lipid rafts and the subsequent generation of cell-mediated cytotoxicity. Pharmacologic and genetic interruption of any element of this RhoA/ROCK/LIM-kinase pathway inhibits both the accumulation of F-actin and lipid raft polarization to the site of target contact and the subsequent delivery of the lethal hit. These data define a specialized role for a RhoA-->ROCK-->LIM-kinase pathway in cytotoxic lymphocyte activation.