The involvement of lipid rafts in the regulation of integrin function.
Integrin activity on cells such as T lymphocytes is tightly controlled. Here we demonstrate a key role for lipid rafts in regulating integrin function. Without stimulation integrin LFA-1 is excluded from lipid rafts, but following activation LFA-1 is mobilised to the lipid raft compartment. An LFA-1 construct from which the I domain has been deleted mimics activated integrin and is constitutively found in lipid rafts. This correlation between integrin activation and raft localisation extends to a second integrin, alpha4beta1, and the clustering of alpha4beta1 is also raft dependent. Both LFA-1 and alpha4beta1-mediated adhesion is dependent upon intact lipid rafts providing proof of the functional relevance of the lipid raft localisation. Finally we find that non-raft integrins are excluded from the rafts by cytoskeletal constraints. The presence of integrin in lipid rafts under stimulating conditions that activate these receptors strongly indicates that the rafts have a key role in positively regulating integrin activity.
Leitinger
Birgit
B
Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, WC2A 3PX, UK.
Hogg
Nancy
N
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002784:Cholesterol / Q000172:deficiency; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D008563:Membrane Lipids / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014407:Tumor Cells, Cultured
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002273:Carcinogens; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D008563:Membrane Lipids; D019384:Nucleic Acid Synthesis Inhibitors; D010703:Phorbol Esters; D020033:Protein Isoforms; D016201:Receptors, Lymphocyte Homing; D013844:Thiazoles; D053778:Thiazolidines; D015638:Cytochalasin D; D002784:Cholesterol; D008274:Magnesium; C037067:latrunculin A