Erk Kinases Link Pre-B Cell Receptor Signaling to Transcriptional Events Required for Early B Cell Expansion

Yasuda, Tomoharu; Sanjo, Hideki; Pagès, Gilles; Kawano, Yoshiaki; Karasuyama, Hajime; Pouysségur, Jacques; Ogata, Masato; Kurosaki, Tomohiro

doi:10.1016/j.immuni.2008.02.015

Cited by 145 publications

(167 citation statements)

References 55 publications

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“…Together with studies showing that Erk and Ras play an important role during the differentiation of pro-B cells into pre-B cells (22)(23)(24)(25), these findings suggest a role for Ras and Erk in both pre-BCR and mature BCR signaling.…”

Section: Significancesupporting

confidence: 64%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Newly generated immature B cells are selected to enter the peripheral mature B-cell pool only if they do not bind (or bind limited amount of) self-antigen. We previously suggested that this selection relies on basal extracellular signal-regulated kinase (Erk) activation mediated by tonic B-cell antigen receptor (BCR) signaling and that this signal can be replaced by an active rat sarcoma (Ras), which are small GTPase proteins. In this study we compared the activity of Ras and Erk in nonautoreactive and autoreactive immature B cells and investigated whether activation of Ras can break tolerance. Our results demonstrate lower levels of active Erk and Ras in autoreactive immature B cells, although this is evident only when these cells display medium/high avidity for self-antigen. Basal activation of Erk in immature B cells is proportional to surface IgM and dependent on sarcoma family kinases, whereas it is independent of B-cell activating factor, IFN, and Tolllike receptor signaling. Ectopic expression of the constitutively active mutant Ras form N-RasD12 in autoreactive cells raises active Erk, halts receptor editing via PI3 kinase, and promotes differentiation via Erk, breaking central tolerance. Moreover, when B cells coexpress autoreactive and nonautoreactive BCRs, N-RasD12 leads also to a break in peripheral tolerance with the production of autoantibodies. Our findings indicate that in immature B cells, basal activation of Ras and Erk are controlled by tonic BCR signaling, and that positive changes in Ras activity can lead to a break in both central and peripheral B-cell tolerance.Src | BAFF

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Section: Significancesupporting

confidence: 64%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Pro-and pre-B cells respond to cooperative pre-BCR and IL-7Ra signaling for optimal proliferation during heavy chain rearrangement (Marshall et al, 1998;Fleming and Paige, 2002), and manipulation of these pathways can affect c-Myc-induced tumor development. For example, recombination activating gene (RAG) is required for pre-BCR surface expression that induces the maturation of pro-to pre-B cells and c-Myc-mediated cellular proliferation (Yasuda et al, 2008). However, transgenic expression of c-Myc in rag2 À/À mice bypasses the requirement for pre-BCR signaling and gives rise to cells with a pre-B-cell phenotype (Habib et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the El-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ra) in a knock-in mouse model (IL-7Ra 449F ) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ra 449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and El-myc mice. We found that the loss of IL-7Ra Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of El-myc-induced B-cell tumors. We showed that the IL-7Ra 449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Elmyc-induced proliferation. This study shows that IL-7Ra Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ra signals in early B-cell development.

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“…16,33 Although signal transduction downstream of pre-BCR remains to be fully characterized, similar signaling complexes are formed following the engagement of BCR and pre-BCR. [34][35][36] Because TLR4 signaling is shown to synergize with BCR-delivered signals during the activation of mature B cells, 37,38 it would not be surprising if the TLR4 signaling pathway also interacts with pre-BCR signaling during pre-B-cell development. Thus, signals mediated by IL-7R, pre-BCR and TLR4 may converge to modulate pre-B-cell maturation.…”

Section: Synergism Of Lps and Il-7 Signals In The Promotion Of Pre-bcmentioning

confidence: 99%

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

Han

Wang

et al. 2013

Cell Mol Immunol

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Lipopolysaccharide (LPS) is known to be a potent activator of mature B cells by signaling through Toll-like receptor 4 (TLR4). Its impact on early B-cell development, however, is not well defined. When comparing to C3H/HeN mice, TLR4-mutant C3H/HeJ mice showed an increase in the number of pro-B and pre-B cells in the bone marrow. When cultured in the presence of IL-7, the proliferation of pro-B and large pre-B cells was significantly inhibited by LPS, possibly due to reduced IL-7 receptor-a (IL-7Ra) expression. Meanwhile, the generation of IgM 1 /IgD 1 B cells was greatly enhanced in IL-7 cultures of pro-B and pre-B cells. Consistent with these results, treatment with LPS facilitated the progression of adoptively transferred B220 1 IgM 2 IgD 2 precursors into IgD 1 cells. Overall, these data suggest that LPS has a profound influence on early B-cell development, which may contribute to the deregulated B-cell development under physiological and pathological conditions such as bacterial infections.

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Erk Kinases Link Pre-B Cell Receptor Signaling to Transcriptional Events Required for Early B Cell Expansion

Cited by 145 publications

References 55 publications

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

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