The role of lipid rafts in T cell antigen receptor (TCR) signalling

Janes, Peter W.; Ley, Steven C.; Magee, Anthony I.; Kabouridis, Panagiotis S.

doi:10.1006/smim.2000.0204

Cited by 405 publications

(343 citation statements)

References 71 publications

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“…The T-cell receptor is a wellstudied example for this. 38 Stimulation of T-cell receptor by antigen-presenting cells triggers its oligomerization. This process is accompanied by the recruitment of the T-cell receptor into raft microdomains leading to the engagement into higher order protein complexes.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Lipid Rafts in Nephrin Phosphorylation and Organization of the Glomerular Slit Diaphragm

Simons

Schwarz

Kriz

et al. 2001

The American Journal of Pathology

146

126

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NPHS1 has recently been identified as the gene whose mutations cause congenital nephrotic syndrome of the Finnish type. The respective gene product nephrin is a transmembrane protein expressed in glomerular podocytes and primarily localized to the glomerular slit diaphragm. This interpodocyte junction functions in the glomerular filtration by restricting the passage of plasma proteins into the urinary space in a size-selective manner. The functional role of nephrin in this filtration process is so far not very well understood. In this study, we show that nephrin associates in an oligomerized form with signaling microdomains, also known as lipid rafts, and that these localize to the slit diaphragm. We also show that the nephrin-containing rafts can be immunoisolated with the 27A antibody recognizing a podocyte-specific 9-Oacetylated GD3 ganglioside. In a previous study it has been shown that the in vivo injection of this antibody leads to morphological changes of the filtration slits resembling foot process effacement. Here, we report that, in this model of foot process effacement, nephrin dislocates to the apical pole of the narrowed filtration slits and also that it is tyrosine phosphorylated. We suggest that lipid rafts are important in the spatial organization of the glomerular slit diaphragm under physiological and pathological conditions. One of the main functions of the kidney is formation of the primary urine in the glomerulus by plasma ultrafiltration. The structural correlate of ultrafiltration is the glomerular capillary wall with its distinctly layered filtration barrier. It consists of the fenestrated vascular endothelium, the glomerular basement membrane, and a layer of morphologically highly specialized epithelial cells, podocytes.Podocytes form a tight network of multiple interdigitating cellular extensions, called foot processes, which are bridged by so-called "slit diaphragms." 1 The filtration barrier is freely permeable for water, small solutes, and ions but does not allow passage for proteins larger than albumin and other large molecules. The charge selectivity in this process has been attributed to the glomerular basement membrane whereas the slit diaphragm supposedly plays a major role in the size selectivity. 2,3 The importance of the filtration barrier is reflected by a number of human diseases in which the filtration barrier function is disrupted resulting in the loss of plasma proteins into the urine. Patients with persistent proteinuria ultimately develop a nephrotic syndrome with a variety of symptoms including edema, hypoalbuminemia, and hyperlipidemia. 4

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Section: Discussionmentioning

confidence: 99%

Involvement of Lipid Rafts in Nephrin Phosphorylation and Organization of the Glomerular Slit Diaphragm

Simons

Schwarz

Kriz

et al. 2001

The American Journal of Pathology

146

126

View full text Add to dashboard Cite

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“…[27][28][29] In eukaryotic cells, many signaling complexes appear to be associated with detergent insoluble lipid microdomains that provide unique physical environments for the concentration of signaling components. [30][31][32][33][34][35] Often it is not known whether cells use microdomains or other mechanisms to organize and assemble signaling components.…”

Section: Signaling Complexesmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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“…The immunological synapse is a highly organized structure that forms at the interface between the antigen presenting cell (APC) and the T cell, and is all-important for T cell activation [2]. Membrane lipid rafts aggregate at the immunological synapse, a prerequisite for signaling through the T cell receptor (TCR) [3]. Lipid rafts, also known as detergent insoluble, glycolipid-enriched complexes (DIGs) or glycosphingolipid enriched membranes (GEMs), are microdomains within the lipid membrane that are enriched in sphingolipids and cholesterol.…”

Section: A Role For Chemokines In the Recruitment And Polarization Ofmentioning

confidence: 99%