Negative regulation of apoptotic death in immature B cells by CD45

Ogimoto, Mami; Katagiri, Tatsuo; Mashima, Keisuke; Hasegawa, Kiminori; Mizuno, Kazuya; Yakura, Hidetaka

doi:10.1093/intimm/6.4.647

Cited by 41 publications

(43 citation statements)

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“…27,29,31 These cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 50 M 2-mercaptoethanol (2-ME), 100 g/mL streptomycin, and 100 U/mL penicillin. CD45 exon 9 knock-out (KO) 38 and C57BL/6 (B6) mice were obtained from Jackson Laboratory (Bar Harbor, ME) and Japan SLC (Hamamatsu, Japan), respectively, and used at 6 to 12 weeks of age.…”

Section: Cell Culturementioning

confidence: 99%

“…29 Briefly, cells (2 ϫ 10 5 /mL) were either left untreated, treated with 5 mM MCD, or treated and allowed to recover, after which they were either left unstimulated or were stimulated for 24 hours with anti-IgM Ab (20 g/mL) and then lysed for 10 minutes at 4°C in buffer containing 10 mM Tris-HCl, pH 8.0, 10 mM EDTA, and 0.5% Triton X-100. After centrifugation, the supernatant was treated first with 100 g/mL RNase for 1 hour at 37°C, and then with 200 g/mL proteinase K in 1% SDS for 2 hours at 50°C.…”

Section: Apoptosis Assaysmentioning

confidence: 99%

“…We previously showed that CD45 exerts a negative regulatory effect on BCR-induced Ca 2ϩ mobilization, activation of c-Jun NH 2 -terminal kinase (JNK) and p38, and growth arrest in immature WEHI-231 cells, 29,30 but exerts a positive regulatory effect on these processes in mature BAL-17 cells. 30, 31 We further showed that, in WEHI-231 cells, CD45 constitutively inhibits Lyn by dephosphorylating both the COOH-terminal and autophosphorylation sites, but that BCR ligation induces phosphorylation of the 2 sites.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic regulation of Src-family kinases by CD45 in B cells

Shrivastava

Katagiri

Ogimoto

et al. 2004

Blood

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CD45 is a key protein tyrosine phosphatase regulating Src-family protein tyrosine kinases (Src-PTKs) in lymphocytes; precisely how it exerts its effect remains controversial, however. We previously demonstrated that CD45 negatively regulates Lyn in the WEHI-231 B-cell line. Here we show that negative regulation by CD45 is physiologically significant in B cells and that some CD45 is constitutively associated with glycolipid-enriched mi- IntroductionUpon B-cell receptor (BCR) ligation, signals are transmitted downstream through multiple pathways, ultimately leading to cell activation, proliferation, death, or anergy. [1][2][3][4] Initiation of such immune responses is driven primarily by activation of Src-family protein tyrosine kinases (Src-PTKs) whose activity is regulated, in part, by phosphorylation of 2 tyrosine residues: the autophosphorylation site, located in the activation loop of the catalytic domain, and the COOH-terminal negative regulatory site. 5 Phosphorylation of the former is a prerequisite for Src-PTK activation. Phosphorylation of the latter by COOH-terminal Src kinase (Csk) results in the intramolecular binding of the phosphotyrosine (PY) in the COOHterminal tail to the Src homology 2 (SH2) domain, yielding a closed conformation in which Src-PTK activity is attenuated. Thus, phosphorylation of the respective regulatory tyrosine residues has opposing effects on Src-PTK activity.CD45, a receptor-type protein tyrosine phosphatase (PTP) exclusively expressed in nucleated hematopoietic cells, is known to be a major regulator of Src-PTK activation and of lymphocyte fate, 6-8 though its precise role in the regulation of Src-PTKs remains controversial. [9][10][11][12][13] One conventional model holds that when Csk phosphorylates the negative regulatory COOH-terminal tyrosine residue, leading to the aforementioned closed and inactive conformation, the dominant role of CD45 is to dephosphorylate this site, setting the stage for antigen receptor signaling to activate Src-PTKs by autophosphorylation. 14,15 This scenario is based on the findings that the COOH-terminal tyrosine residues of Lck and Fyn are hyperphosphorylated and T-cell receptor (TCR) signaling is attenuated in CD45-deficient T-cell lines and in thymocytes from Ptprc-targeted mice. [16][17][18][19][20] Moreover, similar results have also been obtained in B cells. [21][22][23] However, CD45 is also shown to dephosphorylate both of Src-PTK's regulatory tyrosine residues in both T cells 24-26 and B cells, 27,28 thereby inactivating it.We previously showed that CD45 exerts a negative regulatory effect on BCR-induced Ca 2ϩ mobilization, activation of c-Jun NH 2 -terminal kinase (JNK) and p38, and growth arrest in immature WEHI-231 cells, 29,30 but exerts a positive regulatory effect on these processes in mature BAL-17 cells. 30,31 We further showed that, in WEHI-231 cells, CD45 constitutively inhibits Lyn by dephosphorylating both the COOH-terminal and autophosphorylation sites, but that BCR ligation induces phosphorylation of the 2 sites. 27, 2...

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Section: Cell Culturementioning

confidence: 99%

Section: Apoptosis Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynamic regulation of Src-family kinases by CD45 in B cells

Shrivastava

Katagiri

Ogimoto

et al. 2004

Blood

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“…Cells (1.5 ϫ 10 6 ) were suspended in 5 ml of complete medium and either left untreated or stimulated with 5 g/ml anti-IgM Ab for 48 h. The cells were then harvested, washed twice with PBS, and subjected to DNA fragmentation assays (36) and TUNEL assays, as previously described (37).…”

Section: Assays For Apoptosismentioning

confidence: 99%

Src Homology Region 2 Domain-Containing Phosphatase 1 Positively Regulates B Cell Receptor-Induced Apoptosis by Modulating Association of B Cell Linker Protein with Nck and Activation of c-Jun NH2-Terminal Kinase

Mizuno

Tagawa

Mitomo

et al. 2002

The Journal of Immunology

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Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a key mediator in lymphocyte differentiation, proliferation, and activation. We previously showed that B cell linker protein (BLNK) is a physiological substrate of SHP-1 and that B cell receptor (BCR)-induced activation of c-Jun NH2-terminal kinase (JNK) is significantly enhanced in cells expressing a form of SHP-1 lacking phosphatase activity (SHP-1-C/S). In this study, we confirmed that SHP-1 also exerts negative regulatory effects on JNK activation in splenic B cells. To further clarify the role of SHP-1 in B cells, we examined how dephosphorylation of BLNK by SHP-1 affects downstream signaling events. When a BLNK mutant (BLNKΔN) lacking the NH2-terminal region, which contains four tyrosine residues, was introduced in SHP-1-C/S-expressing WEHI-231 cells, the enhanced JNK activation was inhibited. Among candidate proteins likely to regulate JNK activation through BLNK, Nck adaptor protein was found to associate with tyrosine-phosphorylated BLNK and this association was more pronounced in SHP-1-C/S-expressing cells. Furthermore, expression of dominant-negative forms of Nck inhibited BCR-induced JNK activation. Finally, BCR-induced apoptosis was suppressed in SHP-1-C/S-expressing cells and coexpression of Nck SH2 mutants or a dominant-negative form of SEK1 reversed this phenotype. Collectively, these results suggest that SHP-1 acts on BLNK, modulating its association with Nck, which in turn negatively regulates JNK activation but exerts a positive effect on apoptosis.

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“…The tyrosine phosphatase CD45 is required for efficient BCR signal transduction (23,24,(34)(35)(36)(37)(38). As a consequence, CD45 deficiency promotes survival and accumulation of self-reactive B cells in vivo (38).…”

Section: Receptor Editing In B Cells From Hemizygous 3-83igi;h-2 D Mimentioning

confidence: 99%

Different sensitivity to receptor editing of B cells from mice hemizygous or homozygous for targeted Ig transgenes

Braun

Rajewsky

Pelanda

2000

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

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Ig knock-in mice have been used to study the relative contribution of receptor selection versus clonal selection in the control of autoreactive B cells. The anti-MHC class I 3-83Ig knock-in (3-83Igi) mice manifest extensive receptor editing in the presence of H-2 b . However, receptor editing is also observed on the H-2 d background, although reactivity toward this antigen is below detection and its presence does not affect the generation of 3-83Ig ؉ mature B cells in classical 3-83Ig transgenic mice. In this study we have analyzed the contribution of genetic background, B cell receptor signaling, and transgene copy number on the initiation and extent of receptor editing in the 3-83Igi;H-2 d mice. Crossing the 3-83Ig insertion into either CD45-deficient H-2 d mice or onto the BALB͞c background reduces the extent of receptor editing and increases the fraction of 3-83Ig-expressing B cells, indicating that in the original line editing depends on B cell receptor signaling induced by cross-reacting antigen(s). However, receptor editing is still detectable in hemizygous 3-83Igi mice even on the BALB͞c background, on which the 3-83 antibody was originally raised, whereas it is abrogated in homozygous 3-83Igi;H-2 d animals. This latter observation indicates that immature B cells expressing immunoglobulin from single heavy and light chain loci, as they do physiologically, utilize receptor editing for an exquisite quality control of their antigen receptor that may only partly be based on selfreactivity.T he mature B cell population expresses a diversified immunoglobulin (Ig) repertoire able to recognize any foreign antigen. Generation of antigen receptors depends on the combinatorial somatic rearrangement of V (variable), D (diversity), and J (joining) gene segments [the V(D)J recombination process; refs. 1 and 2]. In this way antibodies can be produced that are specific for foreign as well as self antigens. Therefore, the immature B cell repertoire must undergo a selection process to prevent self-reactive cells from distributing throughout the body (3)(4)(5).To analyze the selection process of given Ig specificities, conventional transgenic technology first and ''knock-in'' gene technology later have been used to generate mice whose B cells develop with prerearranged Ig heavy (H) and light (L) chain genes (6). These systems take advantage of the fact that Ig expression from one allele inhibits V(D)J recombination on the second allele, a phenomenon known as allelic exclusion (7). Consequently, expression of the Ig transgenes prevents rearrangement and expression of endogenous Ig genes, promoting the generation of a monospecific B cell population (8-13). The analysis of Ig transgenic mice expressing autoreactive specificities has demonstrated the existence of clonal deletion, clonal anergy, and receptor editing as mechanisms that operate to censor autoreactive B cells (14,15). In Ig knock-in mice receptor editing results in the efficient elimination of autoreactive specificities and the generation of a diversified B cell p...

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Negative regulation of apoptotic death in immature B cells by CD45

Cited by 41 publications

References 0 publications

Dynamic regulation of Src-family kinases by CD45 in B cells

Dynamic regulation of Src-family kinases by CD45 in B cells

Src Homology Region 2 Domain-Containing Phosphatase 1 Positively Regulates B Cell Receptor-Induced Apoptosis by Modulating Association of B Cell Linker Protein with Nck and Activation of c-Jun NH2-Terminal Kinase

Different sensitivity to receptor editing of B cells from mice hemizygous or homozygous for targeted Ig transgenes

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