Identification of the intracytoplasmic region essential for signal transduction through a B cell activation molecule, CD40

Inui, Shigeru; Kaisho, Tsuneyasu; Kikutani, Hitoshi; Stamenkovic, Ivan; Seed, Brian; Clark, Edward A.; Kishimoto, Tadamitsu

doi:10.1002/eji.1830200819

Cited by 85 publications

(46 citation statements)

References 38 publications

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“…A Thr 254 ?Ala mutation (PxQxT? PxQxA) disrupts the motif, preventing TRAF binding to the CD40 tail and thereby abrogating subsequent signalling (Inui et al, 1990;Hu et al, 1994;Rothe et al, 1995;Sarma et al, 1995). In agreement with these data, both TRAF2 and TRAF3 are expressed in epithelial cell lines ( Figure 4a) and expression of a Thr 254 ?Ala CD40 mutant in HeLa cervical epithelial cells abolishes CD40-mediated NF-kB activation and IL6 release.…”

Section: Cd40 Ligation Induces Il6 Via An Nf-kb Mechanismsupporting

confidence: 65%

“…TRAF3 also associates with the cytoplasmic tail of CD40 through a TRAF binding domain which is characterised by a PxQxT core sequence (aa 250 ± 254) essential for interaction. Indeed, a Thr 254 ?Ala mutation diminishes association of TRAFs with CD40 and blocks CD40-mediated NF-kB activation (Inui et al, 1990;Hu et al, 1994;Rothe et al, 1995). In agreement with these reports, expression of the above CD40 mutant in HeLa cells abrogated NF-kB activity and IL6 secretion in response to CD40 ligation.…”

Section: Discussionsupporting

confidence: 52%

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Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

et al. 1997

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Expression of the Epstein ± Barr virus (EBV) transforming LMP1 in B cells activates the transcription factor NF-kB and induces phenotypic changes through two distinct domains in the cytoplasmic C-terminus of the protein. The aa 187 ± 231 domain of LMP1, which is important for growth transformation, binds tumour necrosis factor (TNF) receptor associated factor (TRAF) 1 and TRAF3 and this interaction mediates subsequent signalling events. The TRAFs also associate with CD40, a member of the TNFR family, which upon ligation activates NF-kB and induces phenotypic changes similar to those mediated by LMP1. This study demonstrates that LMP1 expression in carcinoma cell lines and SV40-transformed keratinocytes results in induction of the pleiotropic cytokine interleukin 6 (IL6), an e ect which is also observed upon CD40 ligation. The mechanism by which either LMP1 expression or CD40 ligation induces IL6 production was found to be NF-kB-dependent. Mutational analysis identi®ed domains in the C-terminus of LMP1 which are important for NF-kB activation and IL6 secretion. LMP1 and CD40 share a common PxQxT core TRAF binding motif and mutations in or adjacent to this sequence impaired the ability of LMP1 or CD40 to induce NF-kB activation and IL6 secretion. The importance of TRAF interactions in mediating these e ects was con®rmed using dominant negative TRAF2 and TRAF3 mutants which also identi®ed di erences in the signalling events mediated by the two NF-kB activating domains of LMP1. A20, an anti-apoptotic protein which interacts with TRAF2 and blocks CD40-mediated NF-kB activity, also blocked NF-kB and IL6 secretion in LMP1-transfected epithelial cells. These results suggest that LMP1 regulates IL6 production in epithelial cells in a manner similar to CD40 ligation and implicate TRAFs as common mediators in the transduction of signals generated via the CD40 and LMP1 pathways. As a role for IL6 in regulating epithelial cell growth has previously been suggested, the control of IL6 secretion via the CD40 and LMP1 pathways may have implications for the growth of both normal and transformed epithelial cells.

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Section: Cd40 Ligation Induces Il6 Via An Nf-kb Mechanismsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 52%

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

et al. 1997

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“…In an in vitro model, an anti-CD40 mAb inhibits the growth of CD40 transfectants of routine M12 (B cell) and EL-4 (T cell) lines. Mutational analysis has revealed that Thr TM is essential for signal transduction in this system (48). Although this is a limited analysis, the results indicate that phosphorylation of CD40 by serine/threonine protein kinases is essential for CD40 signaling.…”

Section: Anti-cd40 Mab-induced Changes In Tfosine Phasphorflation In mentioning

confidence: 85%

CD40 signaling pathway: anti-CD40 monoclonal antibody induces rapid dephosphorylation and phosphorylation of tyrosine-phosphorylated proteins including protein tyrosine kinase Lyn, Fyn, and Syk and the appearance of a 28-kD tyrosine phosphorylated protein.

Faris

Gaskin

Parsons

et al. 1994

The Journal of Experimental Medicine

121

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SummaryCD40 plays an important role in B cell activation, proliferation, and Ig class switching. The signal transduction pathway mediated by CD40 was studied using monoclonal antibody (mAb) 626.1 to CD40. Burkitt's lymphoma and Epstein-Barr virus-transformed B cell lines and tonsilar B lymphocytes were treated with the anti-CD40 mAb for various lengths of time. The early events triggered by CD40 were examined by monitoring the changes in tyrosine phosphorylation of cellular proteins with anti-phosphotyrosine mAb. Dephosphorylation of specific proteins ranging between 50-110 kD and the appearance of a 28-kD tyrosine phosphorylated protein were seen within 30 s in human B cell lines. The dephosphorylation was reversed and the 28-kD protein was dephosphorylated in cells stimulated for 1 min. In resting B cells, the appearance of the 28-kD phosphoprotein was observed in 30 s after the addition of the anti-CD40 mAb. The tyrosine phosphorylation of this protein persisted. The patterns of protein tyrosine phosphorylation differed from those induced by an anti-immunoglobulin M mAb. The changes in the state of tyrosine phosphorylation induced by the anti-CD40 mAb were obviated by mAb to CD45, a protein tyrosine phosphatase (PTP) or by the addition of sodium orthovanadate, a broad PTP inhibitor. They were also blocked by protein tyrosine kinase (FFK) inhibitors, herbimycin A and genistein, and PKC and protein serine/threonine kinase inhibitors, H7 and HA1004. In addition, the alteration in the tyrosine phosphorylation ofPTKs Lyn, Fyn, and Syk was directly demonstrated. Engagement of CD40 for 30 s induced a transient decrease in tyrosine phosphorylation of these PTKs. These results indicate that the early events in CD40 signaling involve the complex interaction between PTP and protein kinases. C D40 is a 47-50-kD glycoprotein expressed on B cells and some normal and neoplastic epithelial cells including follicular dendritic cells and thymic epithelium (1-8). The cDNA sequences of both human and murine CD40 show that these glycoproteins are type I transmembrane proteins and contain cysteine-rich extracellular domains followed by serine/threonine-rich regions preceding the transmembrane domain (9, 10). They have significant homology to the members of the nerve growth factor receptor family (9-11).CD40 plays an important role in B cell activation, differentiation, and survival. Heterologous Abs and mAbs to CD40 induce B cell proliferation (1, 2, 4, 12, 13) and the engagement of CD40 by mAb provides a stimulatory signal synergistic with those delivered by IL-4 or Ab to either surface IgM (slgM) 1 or CD20 (2,14,15). An anti-CD40 mAb in the presence of IL-4 promotes long-term B cell growth (16). CD40 also plays a role in the induction of homotypic adhesion (17,18). A mAb to CD40 induces bcl-2 expression and Parts of these results have been presented in abstract form at the Annual Meeting AAP/ASCI/AFCR in

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“…The cDNA for WT, T254A, and Del201 human CD40 have been described [49]. The receptor mutants ¿ T6 and ¿ T2/3/ 6 correspond to P233G/E235A and P233G/E235A/T254A hCD40, respectively [31] and were kind gifts of Drs.…”

Section: Cd40/cd154 Reagentsmentioning

confidence: 99%

Distinct contributions of different CD40 TRAF binding sites to CD154‐induced dendritic cell maturation and IL‐12 secretion

et al. 2003

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The mechanisms by which CD40 controls the maturation and antigen presentation functions of dendritic cells (DC) remains largely undefined in this critical cell type. To examine this question, we have employed retroviral transduction of primary bone marrow-derived mouse DC. Mutation of the distinct binding sites for TNF receptor-associated factor 6 (TRAF6) and for TRAF 2, 3, and 5 in the CD40 cytoplasmic domain revealed their independent contributions to DC maturation and activation of NF-‹ B. In contrast, disruption of the TRAF6 but not the TRAF 2,3,5 binding site markedly decreased IL-12 p40 secretion along with p38 and JNK activation in response to CD154 stimulation. These data document a clear bifurcation of the CD40 signaling cascade in primary DC at the level of the receptor's two distinct and autonomous TRAF binding sites, and reveal the predominant role of the TRAF6 binding site in CD40-induced pro-inflammatory cytokine production by these cells.

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Identification of the intracytoplasmic region essential for signal transduction through a B cell activation molecule, CD40

Cited by 85 publications

References 38 publications

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

CD40 signaling pathway: anti-CD40 monoclonal antibody induces rapid dephosphorylation and phosphorylation of tyrosine-phosphorylated proteins including protein tyrosine kinase Lyn, Fyn, and Syk and the appearance of a 28-kD tyrosine phosphorylated protein.

Distinct contributions of different CD40 TRAF binding sites to CD154‐induced dendritic cell maturation and IL‐12 secretion

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