IgG1 cytoplasmic tail is essential for cell surface expression in Igβ down-regulated cells

Todo, Kagefumi; Koga, Orie; Nishikawa, Miwako; Hara, Masaki

doi:10.1016/j.bbrc.2014.02.037

Cited by 3 publications

(3 citation statements)

References 18 publications

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“…Surface CD79B independent of IgH has been observed in normal mouse B cells 40 and cell lines 41,42 after BCR cross-linking or cognate antigen encounter, and IgG (but not IgM) can be present on the surface of cells lacking the CD79A/B heterodimer. 43,44 These precedents raise the possibility that some fraction of surface CD79B in some GCB-DLBCL lines may not be part of a complete BCR unit, and that surface CD79B staining may overestimate the amount of surface BCR that is generating tonic signals. Although phosphorylation of AKT sites Ser473 or Thr308 is widely used as a surrogate for AKT activity, the reliability of pSer473 in particular has been questioned (eg, for discordance with pThr308 45 or for being rendered unnecessary by phosphorylation of S477 and T479 46 ).…”

Section: Discussionmentioning

confidence: 99%

Tonic B-cell receptor signaling in diffuse large B-cell lymphoma

Havránek¹,

Xu²,

Köhrer³

et al. 2017

Blood

109

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We used clustered regularly interspaced short palindromic repeats/Cas9-mediated genomic modification to investigate B-cell receptor (BCR) signaling in cell lines of diffuse large B-cell lymphoma (DLBCL). Three manipulations that altered BCR genes without affecting surface BCR levels showed that BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to Bruton tyrosine kinase inhibition by ibrutinib, and the activated B-cell (ABC) subtype. Replacing antigen-binding BCR regions had no effect on BCR signaling in GCB-DLBCL lines, reflecting this subtype's exclusive use of tonic BCR signaling. Conversely, Y188F mutation in the immunoreceptor tyrosine-based activation motif of CD79A inhibited tonic BCR signaling in GCB-DLBCL lines but did not affect their calcium flux after BCR cross-linking or the proliferation of otherwise-unmodified ABC-DLBCL lines. CD79A-GFP fusion showed BCR clustering or diffuse distribution, respectively, in lines of ABC and GCB subtypes. Tonic BCR signaling acts principally to activate AKT, and forced activation of AKT rescued GCB-DLBCL lines from knockout (KO) of the BCR or 2 mediators of tonic BCR signaling, SYK and CD19. The magnitude and importance of tonic BCR signaling to proliferation and size of GCB-DLBCL lines, shown by the effect of BCR KO, was highly variable; in contrast, pan-AKT KO was uniformly toxic. This discrepancy was explained by finding that BCR KO-induced changes in AKT activity (measured by gene expression, CXCR4 level, and a fluorescent reporter) correlated with changes in proliferation and with baseline BCR surface density. PTEN protein expression and BCR surface density may influence clinical response to therapeutic inhibition of tonic BCR signaling in DLBCL.

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Section: Discussionmentioning

confidence: 99%

Tonic B-cell receptor signaling in diffuse large B-cell lymphoma

Havránek¹,

Xu²,

Köhrer³

et al. 2017

Blood

109

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“…In contrast, IgG has a longer cytoplasmic tail and can pair with CD79A, and is thus less dependent on CD79B for proper surface expression. 48 Furthermore, targeted mutation of CD79B in mice prevented expression of m heavy chain, but not CD79A, and produced a complete block in B-cell development at the immature B-cell stage. 49 The underlying cause for CD79B overexpression in MCL is not known, but the expression levels seen in MCL cells are within the range of healthy donor mature B cells.…”

Section: Discussionmentioning

confidence: 99%

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

Myklebust

Brody

Kohrt

et al. 2017

Blood

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• Contrasting patterns of basal phosphorylation levels and a-BCR-induced signaling between CLL and MCL tumors.• Direct association between BCR-induced signaling strength and CD79B level, but inverse association with BTK and SYK inhibitor efficacy.Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large Bcell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cg), but had low a-BCR-induced signaling. This contrasted MCL tumors, where a-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, a-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors. (Blood. 2017;129(6):759-770)

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“…Based on previous reports that the concomitant expression of Igα and Igβ is required for the surface expression of IgM 4 5 6 , it can be assumed that the down-regulation of Igβ may contribute to the prompt clearance of surface IgM BCRs, most of which remain unmutated, in B cells that in turn start expressing mutated IgG in turn. Supporting this assumption, we have recently found that membrane-attached IgG1 can be expressed on the cell surface of GP2-293 cells and Igβ down-regulated Ramos B cells, in contrast to IgM which could not be expressed on the surface of these cells 32 .…”

Section: Discussionmentioning

confidence: 81%

Modulation of Igβ is essential for the B cell selection in germinal center

Todo

Koga

Nishikawa

et al. 2015

Sci Rep

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The positive and negative selection of antigen-reactive B cells take place in the germinal center (GC) during an immune responses. However, the precise molecular mechanisms underlying these selection machineries, including the involvement of antigen receptor signaling molecules, remain to be elucidated. We found that expression levels of Igα and Igβ, which are the essential components of B cell antigen-receptor complex, were differentially regulated in GC B cells and that the expression of Igβ was more prominently down-regulated in a portion of GC B cells. The suppression of Igβ down-regulation reduced the number of GL7+GC B cells and the affinity maturation in T-dependent responses was markedly impaired. In addition, the disease phenotypes in autoimmune-prone mice were ameliorated by blocking of Igβ down-regulation. These results suggest that Igβ down-regulation is involved in the normal positive selection in GC and the accumulation of autoreactive B cells in autoimmune-prone mice.

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IgG1 cytoplasmic tail is essential for cell surface expression in Igβ down-regulated cells

Cited by 3 publications

References 18 publications

Tonic B-cell receptor signaling in diffuse large B-cell lymphoma

Tonic B-cell receptor signaling in diffuse large B-cell lymphoma

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

Modulation of Igβ is essential for the B cell selection in germinal center

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