Translocation of the B Cell Antigen Receptor into Lipid Rafts Reveals a Novel Step in Signaling

Cheng, Paul C.; Brown, Bruce K.; Song, Wenxia; Pierce, Susan K.

doi:10.4049/jimmunol.166.6.3693

Cited by 132 publications

(113 citation statements)

References 40 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…In fact, the recruitment of CD40 into lipid rafts is shown not to require a specific CD40-induced signal because cytoplasmic tail-truncated CD40 molecules easily translocate into these microdomains. Similar findings were reported for other immune receptors such as BCR [35,36] and TCR [37,38]. Indeed, initial studies concerning the mechanism of BCR raft association showed that signalingincompetent mutant BCR translocated to lipid rafts upon receptor oligomerization suggesting that the signaling function of the BCR does not appear essential for translocation to lipid rafts [36].…”

Section: Discussionsupporting

confidence: 77%

“…Similar findings were reported for other immune receptors such as BCR [35,36] and TCR [37,38]. Indeed, initial studies concerning the mechanism of BCR raft association showed that signalingincompetent mutant BCR translocated to lipid rafts upon receptor oligomerization suggesting that the signaling function of the BCR does not appear essential for translocation to lipid rafts [36]. Consistent with this finding, the treatment of B cells with the Srcfamily kinase inhibitors, PP1 or PP2, failed to block BCR translocation [35,36].…”

supporting

confidence: 79%

“…Indeed, initial studies concerning the mechanism of BCR raft association showed that signalingincompetent mutant BCR translocated to lipid rafts upon receptor oligomerization suggesting that the signaling function of the BCR does not appear essential for translocation to lipid rafts [36]. Consistent with this finding, the treatment of B cells with the Srcfamily kinase inhibitors, PP1 or PP2, failed to block BCR translocation [35,36]. It was proposed that cell signaling events, such as protein phosphorylation, Ca 21 mobilization/influx, cytoskeleton rearrangement and phosphorylation of TCR components, might be necessary determinants for the recruitment of the CD3/TCR complex into lipid rafts [37].…”

Section: Discussionmentioning

confidence: 99%

“…It is of particular interest that the tyrosine phosphatase CD45 is specifically excluded from lipid rafts in B cells [27,36,43] and T cells [27,31,44]. While general molecular requirements for raft exclusion are not well understood, the CD45 transmembrane domain is sufficient to re-target otherwise raft-associated proteins to non-raft membranes.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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: Discussionsupporting

confidence: 77%

supporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…BCR signals as a consequence of concentrating BCR-associated Src family tyrosine kinases to promote their trans-phosphorylation and activation (39,40) and to promote localization of the BCR complex into liquid-ordered, cholesterol/glycosphingolipid-enriched compartments of the plasma membrane known as membrane rafts that contain high local concentrations of many of the positive regulators of the signaling cascade (41)(42)(43)(44)(45)(46). However, if pre-BCR signaling does drive B cell development in a ligandindependent fashion, it would suggest that pre-BCR signaling occurs independently of receptor aggregation.…”

Section: Electron Microscopic Analysis Of Primary Pro-b Cellsmentioning

confidence: 99%

Basal Igα/Igβ Signals Trigger the Coordinated Initiation of Pre-B Cell Antigen Receptor-Dependent Processes

Fuentes‐Pananá

Bannish

Shah

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

The pro-B to pre-B transition during B cell development is dependent upon surface expression of a signaling competent pre-B cell Ag receptor (pre-BCR). Although the mature form of the BCR requires ligand-induced aggregation to trigger responses, the requirement for ligand-induced pre-BCR aggregation in promoting B cell development remains a matter of significant debate. In this study, we used transmission electron microscopy on murine primary pro-B cells and pre-B cells to analyze the aggregation state of the pre-BCR. Although aggregation can be induced and visualized following cross-linking by Abs to the pre-BCR complex, our analyses indicate that the pre-BCR is expressed on the surface of resting cells primarily in a nonaggregated state. To evaluate the degree to which basal signals mediated through nonaggregated pre-BCR complexes can promote pre-BCR-dependent processes, we used a surrogate pre-BCR consisting of the cytoplasmic regions of Igα/Igβ that is targeted to the inner leaflet of the plasma membrane of primary pro-B cells. We observed enhanced proliferation in the presence of low IL-7, suppression of VH(D)JH recombination, and induced κ light (L) chain recombination and cytoplasmic κ L chain protein expression. Interestingly, Igα/Igβ-mediated allelic exclusion was restricted to the B cell lineage as we observed normal TCRαβ expression on CD8-expressing splenocytes. This study directly demonstrates that basal signaling initiated through Igα/Igβ-containing complexes facilitates the coordinated control of differentiation events that are associated with the pre-BCR-dependent transition through the pro-B to pre-B checkpoint. Furthermore, these results argue that pre-BCR aggregation is not a requirement for pre-BCR function.

show abstract

The influence of CD40 on the association of the B cell antigen receptor with lipid rafts in mature and immature cells

Malapati

Pierce

2001

Eur. J. Immunol.

Self Cite

View full text Add to dashboard Cite

Cholesterol‐ and sphingolipid‐rich membrane microdomains termed lipid rafts appear to play a central role in B cell activation. In mature B cells, signaling through the B cell antigen receptor(BCR) is initiated from within rafts and leads to activation. In immature B cells, the BCR is excluded from rafts and signaling leads to apoptosis. CD40, a member of the tumor necrosis receptor family, is expressed by B cells throughout development and has been shown to influence the results of the engagement of antigen by the BCR in both mature B and immature B cells. Here evidence is provided that CD40 is excluded from the lipid rafts of both mature and immature B cells and remains excluded from rafts even after cross‐linking. Nevertheless, in mature B cells CD40 signaling influences the association of the BCR with rafts resulting in an increase in the amount of BCR that translocates into rafts following ligand binding and a subsequent acceleration of the movement of the BCR from rafts. In immature B cells, the cross‐linked BCR remains excluded from rafts in the presence of CD40 signaling, conditions under which BCR‐induced apoptosis is blocked. These results indicate that CD40 functions outside lipid rafts to influence raft‐dependent events in mature B cells and raft‐independent events in immature B cells.

show abstract

Translocation of the B Cell Antigen Receptor into Lipid Rafts Reveals a Novel Step in Signaling

Cited by 132 publications

References 40 publications

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

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

Basal Igα/Igβ Signals Trigger the Coordinated Initiation of Pre-B Cell Antigen Receptor-Dependent Processes

The influence of CD40 on the association of the B cell antigen receptor with lipid rafts in mature and immature cells

Contact Info

Product

Resources

About