A Role for Lipid Rafts in B Cell Antigen Receptor Signaling and Antigen Targeting

Cheng, Paul C.; Dykstra, Michelle; Mitchell, Richard N.

doi:10.1084/jem.190.11.1549

Cited by 437 publications

(439 citation statements)

References 51 publications

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“…Previous studies on whether CD45 translocates into LRs have yielded inconsistent results. The results of some studies have suggested that CD45 is excluded, while others have suggested that human leukemia cells and granulocytes transiently express CD45 in LRs (14,(31)(32)(33)(34). More recently, we observed that CD45 translocates into LRs in T cells from patients with SLE but not healthy controls (35).…”

Section: Discussionmentioning

confidence: 66%

“…Following engagement by antigen, the BCR complex translocates into cholesterol-and glycosphingolipidenriched plasma membrane microdomains known as lipid rafts (LRs), followed by phosphorylation by Src kinases. One theory suggests that LRs act as platforms for proximal signaling (13)(14)(15). In addition to translocated BCR, LRs carry Src protein tyrosine kinases (PTKs), glycosylphosphatidylinositol-anchored proteins, and heterotrimeric G proteins.…”

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confidence: 99%

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Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Flores-Borja¹,

Kabouridis²,

Jury³

et al. 2007

Arthritis & Rheumatism

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Objective. B lymphocytes from patients with systemic lupus erythematosus (SLE) exhibit defective intracellular signaling, hyperactivity, and autoantibody production. Recent evidence indicates a reduced expression of Lyn kinase, a negative regulator of B cell signaling, and reduced translocation of Lyn into membrane signaling domains in SLE. The present study was undertaken to investigate the causes of this altered regulation of Lyn by assessing the expression levels of regulatory molecules and their translocation into the signaling domains of SLE B lymphocytes.Methods

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Flores-Borja¹,

Kabouridis²,

Jury³

et al. 2007

Arthritis & Rheumatism

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“…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%

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

et al. 2011

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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...

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“…31 In total, 10 mg each of biotin a-IgM and biotin a-CD19 or biotin rat IgG2a and biotin IgA were added and incubated for 30 min on ice. Avidin (5 mg/ml) was added for an additional 30 min on ice.…”

Section: Immunoprecipitationmentioning

confidence: 99%

Expression of the mouse fragilis gene products in immune cells and association with receptor signaling complexes

et al. 2006

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The mouse genome possesses five genes encoding proteins homologous to human Leu-13. The Leu-13 protein associates with immune cell receptor activation complexes: a monoclonal antibody against Leu-13 induces T and B cells to form homotypic aggregates, inhibits activation-induced proliferation and induces the shedding of L-selectin. The mouse fragilis proteins have not been previously analyzed as components of the immune response. Antibody and nucleic acid reagents were generated that are specific for each of the five fragilis gene products. Expression of some of these genes (fragilis and fragilis3) is wide spread in a variety of mouse immune (and nonimmune) tissues while others (fragilis5) appear to be much more restricted. These proteins have been predicted to span the membrane twice with both amino-and carboxyl-terminal sequences extracellular: we show that a highly conserved loop of the protein between the transmembrane domains is intracellular. The fragilis proteins are associated with tetraspanin proteins CD81 and CD9: B cell activation positions fragilis into lipid rafts along with the CD81, CD19, and CD21. The mouse functional equivalent to human Leu-13 may not be single gene product, but instead may require the contribution of multiple fragilis proteins.

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A Role for Lipid Rafts in B Cell Antigen Receptor Signaling and Antigen Targeting

Cited by 437 publications

References 51 publications

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

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

Expression of the mouse fragilis gene products in immune cells and association with receptor signaling complexes

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