Membrane rafts and signaling by the multichain immune recognition receptors

Langlet, Claire; Bernard, Anne‐Marie; Drevot, Philippe; He, Hai-Tao

doi:10.1016/s0952-7915(00)00084-4

Cited by 223 publications

(170 citation statements)

References 54 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…The crucial role of lipid rafts in the signal transduction of several receptors, such as BCR, TCR and other members of the multichain immune recognition receptor family, has been well documented [29][30][31]. In each case, the lipid rafts concentrate the Src-family kinase (Lyn, Fyn and Lck among others) that initiates signaling and the immune receptors are excluded from the lipid rafts in resting or inactivated cells [32,33]. The binding of multivalent ligands induces the oligomerization of these receptors, resulting in the translocation of the receptors into lipid rafts where the tyrosine residues within the immunoregulatory tyrosine activation motifs (ITAMs) are phosphorylated [27,34].…”

Section: Discussionmentioning

confidence: 99%

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

et al. 2011

View full text Add to dashboard Cite

CanadaCD40, a member of the TNF receptor family, is expressed on a variety of immune and nonimmune cells. Its interaction with its ligand, CD154, plays a pivotal role in humoral and cellmediated immunity. A low level of CD40 is constitutively associated within membrane lipid rafts and, upon engagement, this level is significantly enhanced. In this study, our objective is to evaluate the process of CD40/lipid raft association in terms of the signals required for its initiation and the resulting biological outcomes. Here, we show the CD40/lipid raft association to be independent of PI-3-kinase, Src family kinases and p38 MAPK pathways. Moreover, CD40 lacking its intracellular domain, which is usually required for CD40-mediated signaling, still localizes to lipid rafts upon engagement, confirming that the CD40/ lipid raft association is independent of signaling events. As to the biological outcomes of the CD40/lipid raft association, we show that disrupting lipid raft integrity selectively abolishes CD40-mediated Akt phosphorylation. In addition, replacing the transmembrane domain of CD40 with that of CD45 (a protein excluded from lipid rafts) dramatically reduced CD40-mediated Akt phosphorylation and B7.1 upregulation, while not influencing p38, ERK and JNK activation. Together, these findings clarify the requirements for CD40/lipid raft association and the signals triggered upon CD40 engagement by CD154.Keywords: CD40 . Lipid rafts . Signaling . Transmembrane domain Supporting Information available online IntroductionInteraction between the TNFR, CD40 and its ligand CD154 drives crucial steps in humoral immune responses [1][2][3]. Notably, the CD40/CD154 interaction is critical for the affinity maturation of immunoglobulins (Ig), the development of long-lived plasma B cells and the clonal expansion of memory B cells [1,4,5]. In the absence of intrinsic tyrosine kinase activity, CD40 transmits its intracellular signal via recruitment of several adaptor proteins, such as JAK3 [6] and TNFR-associated factor (TRAF) proteins [5], to specific domains in the CD40 cytoplasmic tail [4,[7][8][9]. This results in the activation of members of the Src kinase family (such as Lyn and Fyn), and other protein tyrosine kinases (such as Syk and Btk) [10,11]; the activation of PI-3 kinase and phospholipase Cg2 [11] and the activation of the MAP kinases p38, JNK and ERK [12][13][14].Lipid rafts are detergent-resistant plasma membrane microdomains that are enriched in cholesterol and sphingolipids. Being 2358scaffolds of many signaling effectors including lipid-anchored proteins (such as Thy-1 and alkaline phosphatase) and signaling molecules (such as some Src kinase family members), lipid rafts act as platforms to initiate and regulate signal transduction processes in many cellular models [15,16]. Engagement of CD40 molecules leads to CD40 clustering into ceramide-enriched lipid rafts of living human B cells [17,18]. Common early events following CD40 clustering in mouse B cells [19] and in human dendritic cells [20] include Lyn act...

show abstract

Section: Discussionmentioning

confidence: 99%

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

et al. 2011

View full text Add to dashboard Cite

show abstract

“…It is well characterized that lipid rafts provide a platform for many signaling events for immune response in the cells. These microdomains are known to contain mediator such as Src family tyrosine kinase and adaptor protein [40][41][42]. Since CD154 is translocated toward these cholesterol-rich domains, we expected that there are necessary at least in part for the signaling mediated through CD154.…”

Section: Discussionmentioning

confidence: 99%

Critical role of lipid rafts in CD154‐mediated T cell signaling

et al. 2010

View full text Add to dashboard Cite

Although signal pathways triggered via the CD40 molecule are well characterized, those induced via CD154 are less known. This study demonstrates that engagement of CD154 in Jurkat D1.1 cells with soluble CD40 leads to PKC a and d activation, calcium mobilization, and phosphorylation of the Map kinases ERK1/2 and p38. Such response is accompanied by significant recruitment of CD154 into lipid rafts. Disruption of lipid rafts integrity with nystatin or methyl b-cyclodextrin abrogated PKCa PKCd and p38 phosphorylation, but had no effect on ERK1/2 phosphorylation. Inhibition of PKC activation completely abolished p38 phosphorylation but had no effect on ERK1/2 phosphorylation, suggesting that localization of CD154 within lipid rafts is an absolute requirement for CD154-induced PKCaand PKCd-dependent p38 phosphorylation. Furthermore, CD154 acts as co-stimulator for the production of IL-2 in an APC-superantigen-T-cell activation model. The results obtained demonstrate for the first time, that lipid rafts are of immunological relevance for CD154-triggered signals, and reinforce the importance of CD154 in T-cell activation.Key words: CD154 . Lipid rafts . Signaling . T lymphocytes Introduction CD154 is a type II transmembrane protein, member of the TNF superfamily, originally detected on the surface of stimulated CD4 1 T cells. Since then, CD154 was found on the surface of activated CD8 1 T cells, gd T cells, B cells, basophils, mast cells, macrophages, dendritic cells, activated platelets, and nonhematopoietic cells such as endothelial cells and fibroblasts [1][2][3][4][5][6][7]. In addition to its transmembrane form, CD154 is also released as a soluble protein by cleavage of the extracellular domain [8,9]. CD154 acts as a ligand for its classical receptor CD40 that is expressed on various cell types of hematopoietic and nonhematopoietic origin such as B cells, macrophages, dendritic cells, platelets, and endothelial and epithelial cells [5]. Recently, three other functional receptors for CD154 have been described, namely the integrins aIIbb3 [6], a5b1 [10], and Mac-1 [11].CD154 is a crucial costimulatory molecule for the development of both humoral and cellular immune responses [5], and plays an important role in the development and/or maintenance of autoimmune and inflammatory diseases [12][13][14][15]. The absence of CD154 leads to hyper-IgM syndrome, abrogation of germinal center formation and failure of B cells to proliferate and differentiate [5,16].The downstream signals triggered via CD40 molecule are extensively studied [5]. However, the signaling pathways linked to CD154 remain poorly known. Previous studies indicate that CD154 accumulate at T cell-APC contact sites in the immunological synapse [17], and that ligation of CD154 on T cells with specific Ab triggers the activation of src kinases, PKC, and MAP kinases [18][19][20], leading to cytokines secretion [21,22] 770CD3-induced T-cell proliferation [23] and apoptosis [22]. However, the precise mechanism by which CD154-triggered signaling is accomplished r...

show abstract

“…[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%

“…Data from microscopy, covalent cross-linking, and x-ray crystallography experiments have revealed that cell surface receptors from many structural classes assemble into multi-receptor complexes; these include some heptahelical G-protein coupled receptors (GPCRs), [36][37][38] methyl-accepting chemotaxis proteins (MCPs), [39] gated ion channels, [40] receptor protein tyrosine kinases (RPTKs), [41,42] and multichain immune recognition receptors (MIRRs). [22,33,35,[43][44][45] The size of these ensembles varies: Some complexes are composed of two receptors while others contain thousands. Some receptors, [46][47][48] including the ryanodine receptor [40] and MCPs, [39] are so highly concentrated that they dominate certain subcellular regions.…”

Section: Signaling Complexesmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

View full text Add to dashboard Cite

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.

show abstract

Membrane rafts and signaling by the multichain immune recognition receptors

Cited by 223 publications

References 54 publications

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

Critical role of lipid rafts in CD154‐mediated T cell signaling

Synthetic Multivalent Ligands as Probes of Signal Transduction

Contact Info

Product

Resources

About