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 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.
Lou
Z
Z
Department of Pharmacology, Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA.
Billadeau
D D
DD
Savoy
D N
DN
Schoon
R A
RA
Leibson
P J
PJ
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion; D016764:Cell Polarity; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D054461:Lim Kinases; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000648:ultrastructure; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
D000199:Actins; D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein