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Cholesterol depletion disrupts lipid rafts and modulates the activity of multiple signaling pathways in T lymphocytes

Kabouridis, PS; Janzen, J; Magee, AL; Ley, SC; (2000) Cholesterol depletion disrupts lipid rafts and modulates the activity of multiple signaling pathways in T lymphocytes. European Journal of Immunology , 30 (3) 954 - 963.

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Abstract

Lipid rafts are specialized plasma membrane microdomains, in which glycosphingolipids and cholesterol are major structural components. In T lymphocytes, several signaling proteins are associated with lipid rafts including the protein tyrosine kinase LCK and the adapter protein LAT. To investigate their importance in T cell signaling, lipid rafts were disrupted by depleting cholesterol with methyl-B-cyclodextrin (MβCD). This transiently induced tyrosine phosphorylation of multiple proteins, including the ZAP-70 tyrosine kinase, its associated T cell antigen receptor ζ chain, LAT and phospholipase Cγ1. Tyrosine phosphorylation was dependent on expression of LCK in lipid rafts. Depletion of cholesterol also resulted in activation of the Ras-ERK pathway. This was largely dependent on phorbol ester-sensitive protein kinase C (PKC) and the PKC-θ isoform translocated to the plasma membrane following MβCD treatment. MβCD did not stimulate intracellular Ca fluxes; however, consistent with its ability to stimulate Ras, MβCD synergized with a Ca ionophore to induce formation of the transcription factor NF-AT. These data indicate a crucial role for cholesterol in the regulation of signaling pathways in T cells, which is likely to reflect its importance in the formation of plasma membrane lipid rafts.

Type:Article
Title:Cholesterol depletion disrupts lipid rafts and modulates the activity of multiple signaling pathways in T lymphocytes
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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