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| Item Type: | Article |
|---|---|
| Title: | Geranylgeranylation but not GTP loading determines rho migratory function in T cells |
| Creators Name: | Waiczies, S., Bendix, I., Prozorovski, T., Ratner, M., Nazarenko, I., Pfueller, C.F., Brandt, A.U., Herz, J., Brocke, S., Ullrich, O. and Zipp, F. |
| Abstract: | Rho GTPases orchestrate signaling pathways leading to cell migration. Their function depends on GTP loading and isoprenylation by geranylgeranyl pyrophosphate (GGpp). In this study, we show that in human T cells, geranylgeranylation-and not GTP loading-is necessary for RhoA-mediated downstream events. As a result of GGpp depletion with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin, RhoA was sequestered from the membrane to the cytosol and, notwithstanding increased GTP loading, the constitutive activation of its substrate Rho-associated coiled-coil protein kinase-1 was blocked. In line with this, T cells expressing increased GTP-RhoA failed to form an intact cytoskeleton and to migrate toward a chemokine gradient. In vivo treatment with atorvastatin in the rodent model of multiple sclerosis markedly decreased the capacity of activated T cells to traffic within the brain, as demonstrated by multiphoton analysis. Thus, tethering of RhoA to the membrane by GGpp is determinant for T cell migration and provides a mechanism for preventing T cell infiltration into inflamed compartments by 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. |
| Keywords: | Apoptosis, Brain, Caspase 3, Cell Line, Cell Movement, Cytoskeleton, Cytosol, Enzyme Activation, Guanosine Triphosphate, Phenalenes, Polyisoprenyl Phosphates, Prenylation, Protein Binding, rho-Associated Kinases, rhoA GTP-Binding Protein, T-Lymphocytes, Animals, Mice |
| Source: | Journal of Immunology |
| ISSN: | 0022-1767 |
| Publisher: | American Association of Immunologists |
| Volume: | 179 |
| Number: | 9 |
| Page Range: | 6024-6032 |
| Date: | 1 November 2007 |
| Official Publication: | http://www.jimmunol.org/cgi/content/abstract/179/9/6024 |
| PubMed: | View item in PubMed |
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