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 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 sign...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.167.10.5749