Rac is involved in early TCR signaling.
The GTPase Rac controls signaling pathways often related to actin polymerization in various cell types. In T lymphocytes, Rac is activated by Vav, a major component of the multiprotein transduction complex associated to the TCR. Although profound signaling defects have been observed in Vav-deficient mice, a role of Rac in the corresponding early TCR signaling has not been tested directly. This question was investigated in Jurkat T cells transfected with either a dominant-negative (RacN17) or a constitutively active (RacV12) form of Rac. In T cells expressing either RacN17 or RacV12, the anti-CD3-induced Ca2+ response and production of inositol-1,4,5-trisphosphate were inhibited. The basal level of phosphatidylinositol-4,5-bisphosphate was not significantly diminished by Rac mutants. The major inhibitory effect of Rac mutants on Ca2+ signaling is exerted on the activity of phospholipase C-gamma and, before that, on the phosphorylation of ZAP-70 and of the linker molecule for activation of T cells, LAT. An anti-CD3-induced increase in actin polymerization was observed in control cells but not in cells transfected with a Rac mutant. In addition, latrunculin, which binds to monomeric actin, simultaneously inhibited basal and CD3-induced actin polymerization and Ca2+ signaling. These findings suggest a link between the effects exerted by Rac mutants on cortical actin polymerization and on TCR signaling. Rac cycling between its GTP- and GDP-bound states is necessary for this signaling. Alterations observed in early TCR-dependent signals suggest that Rac contributes to the assembly of the TCR-associated multiprotein transduction complex.
Arrieumerlou
C
C
Laboratoire d'Immunologie Cellulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7627, Centre Hospitalier Pitié-Salpêtrière, Paris, France.
Randriamampita
C
C
Bismuth
G
G
Trautmann
A
A
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D017252:CD3 Complex / Q000502:physiology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D003599:Cytoskeleton / Q000276:immunology / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000648:ultrastructure; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017252:CD3 Complex; D019269:Phosphatidylinositol 4,5-Diphosphate; D011948:Receptors, Antigen, T-Cell; D013844:Thiazoles; D053778:Thiazolidines; D014443:Tyrosine; D015544:Inositol 1,4,5-Trisphosphate; D020744:rac GTP-Binding Proteins; C037067:latrunculin A; D002118:Calcium