Role for lipid rafts in regulating interleukin-2 receptor signaling

Abstract

IntroductionLipid rafts are plasma membrane microdomains postulated to function in signaling and membrane trafficking. [1][2][3] Lipid rafts are enriched in gangliosides (glycosphingolipids) and cholesterol, which form liquid-ordered domains of decreased membrane fluidity. The long, saturated acyl chains of gangliosides impart a high degree of order further stabilized by intercalating cholesterol molecules, leading to the insolubility of lipid rafts in nonionic detergents. Lipid rafts can be isolated based on their detergent insolubility and low-buoyancy density using discontinuous sucrose gradient ultracentrifugation of nonionic detergent lysates. Lipid rafts are not artifacts of detergent extraction. They have been detected in living cells using chemical cross-linking and fluorescence resonance energy transfer. 4,5 The modification of proteins with saturated acyl groups can result in their localization within lipid rafts. Thus, these microdomains are enriched in glycosyl-phosphatidyl-inositol anchored proteins (GPI-AP) and in many signaling molecules such as Src family protein tyrosine kinases (PTKs), the adaptor protein LAT, heterotrimeric and small G-proteins, and phosphoinositides. 3 In addition, several transmembrane receptors are inducibly recruited to or stabilized within lipid rafts, including T-cell receptor (TCR), B-cell receptor (BCR), and Fc⑀RI. 2 Subsequent activation of signaling molecules in lipid rafts may facilitate signaling through these immunoreceptors. Lipid rafts may act to segregate molecules in the plasma membrane and to regulate signaling through the spatial coordination of intermolecular associations.Stimulation of T cells through TCR results in the activation of multiple signaling pathways, leading to interleukin-2 (IL-2) responsiveness and the secretion of IL-2 and resulting in autocrine cell growth. 6 The high-affinity receptor for IL-2 is composed of the IL-2R␣ chain, which functions solely in IL-2 binding, and IL-2R␤ and IL-2R␥ c , which contribute to IL-2 binding and mediate signal transduction. 7 IL-2-induced proliferation requires activation of the Janus family kinases JAK1 and JAK3, which are constitutively associated with IL-2R␤ and IL-2R␥, respectively. 8,9 Ligandinduced IL-2R aggregation leads to the juxtaposition of JAK1 and JAK3, resulting in their phosphorylation and activation. Subsequent phosphorylation of tyrosine residues in receptor chains leads to the SH2-domain-mediated recruitment of signal transducer and activator of transcription (STAT) proteins STAT5a and STAT5b. 7 JAK-mediated phosphorylation of STAT proteins leads to their dimerization by SH2 domain-phosphotyrosine interactions and their translocation to the nucleus, where STAT proteins regulate gene transcription. Signaling through the IL-2R also induces the recruitment and activation of phosphatidylinositol 3 kinase (PI3K), which is implicated in IL-2-mediated proliferation and survival through its downstream effector protein kinase B/Akt. 10,11 In addition, the tyrosine phosphorylation of IL-2R␤ results i...

A Role for Interleukin-12 in the Regulation of T Cell Plasma Membrane Compartmentation

“…It has been reported that IL-2 pulls out the ␣ chain from rafts to bind the ␤ and ␥ chain of the IL-2 receptor complex in soluble fractions (50). Hence, interleukins are involved in the rules governing the inclusion and exclusion of proteins into rafts.…”

The Cell-Cell Adhesion Molecule Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Inhibits IL-2 Production and Proliferation in Human T Cells by Association with Src Homology Protein-1 and Down-Regulates IL-2 Receptor

“…In one report, the localization of IL-2R␣, but not IL-2R␤ and ␥ to membrane rafts has been reported (37), but in another report all three subunits were localized to lipid rafts (38). In addition, one report showed that Abs to GM1, which is localized to lipid rafts, inhibited IL-2-mediated proliferation (37). Based on our study, we predict that IL-2R clustering will lead to recruitment of the ␤ and ␥ subunits into lipid raft domains, because CEACAM1 appears to reside within these microdomains, and the GM1 inhibition data are consistent with this conclusion.…”

IL-2 and IL-15 receptor α-subunits are coexpressed in a supramolecular receptor cluster in lipid rafts of T cells

“…Integrity of lipid rafts is also essential for IL-2-mediated signaling (12,13). Lipid rafts may promote the formation and cytokine-specific modulation of IL-2R͞IL-15R complexes and ␤-and ␥ c -subunit ''switching'' between IL-2 and IL-15 receptors.…”