Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival

Starlets, Diana; Gore, Yael; Binsky, Inbal; Haran, Michal; Harpaz, N; Shvidel, Lev; Becker-Herman, Shirly; Berrébi, Alain; Shachar, Idit

doi:10.1182/blood-2005-11-4334

Cited by 263 publications

(269 citation statements)

References 43 publications

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“…Moreover, we demonstrated recently that CD74 stimulation with an agonistic CD74 antibody leads to NF-B activation, enabling entry of the stimulated B cells into the S phase, an increase in DNA synthesis, cell division, and augmented expression of members of the Bcl-2 protein family. Thus, these findings indicate that surface CD74 functions as a survival receptor (13).…”

mentioning

confidence: 79%

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

Binsky

Haran

Starlets

et al. 2007

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

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166

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Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-B activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8-dependent survival pathway.apoptosis ͉ invariant chain B cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of CD5 ϩ B lymphocytes in peripheral blood, lymphoid organs, and bone marrow (1). The hallmark of the disease is decreased apoptosis, resulting in accumulation of these malignant cells. Previous studies have shown that chronic lymphocytic leukemia (CLL) lymphocytes express relatively large amounts of mRNA for CD74, which is the cell-surface form of invariant chain (Ii), as compared with normal B cells (2, 3). CD74 is a nonpolymorphic type II integral membrane protein, which was originally thought to function mainly as an MHC class II chaperone (4). However, CD74 recently was found to play an additional role as an accessory-signaling molecule. In macrophages, CD74 demonstrates high-affinity binding to the proinflammatory cytokine, macrophage migration-inhibitory factor (MIF). MIF binds to the extracellular domain of CD74; this complex is required for MIF-mediated MAPK activation and cell proliferation (5). Moreover, the bacterium Helicobacter pylori was shown to bind to CD74 on gastric epithelial cells and to stimulate IL-8 production (6).In a previous study, we showed that CD74 is involved directly in shaping the B cell repertoire (7, 8) by a pathway leading to the activation of transcription mediated by the NF-B p65/RelA homodimer and its coactivator, TAFII105 (9). NF-B activation is mediated by the cytosolic region of CD74 (CD74-ICD), which translocates to the cell nucleus (10). This signal is terminated by degradation of the active CD74-ICD fragment (11,12). Moreover, we demonstrated recently that CD74 stimulation with an agonistic CD74 antibody leads to NF-B activation, enabling entry of the stimulated B cells into the S phase, an increase in DNA synthesis, cell division, and augmented expression of members of the Bcl-2 protein family. Thus, these findings indicate that surface CD74 functions as a survival receptor (13).In the present study, we sought to determine whether CD74 functions as a survival receptor in B-CLL cells. Our results show that MIF-induced CD74 activation initiates a signaling cascade that results in secr...

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mentioning

confidence: 79%

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

Binsky

Haran

Starlets

et al. 2007

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

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166

154

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“…These include tissue factor, the initiator of the extrinsic coagulation cascade, adhesion molecules such as ICAM-1 and VCAM-1 that are required for leukocyte recruitment, CD24, a receptor for P-selectin (32), and the chemokine receptor CXCR7 (chemokine orphan receptor 1). Furthermore, CD74, an accessory signaling receptor resulting in NF-B activation and cell survival (33), and the activation-associated receptor CD69 are upregulated upon infection with C. albicans. Other over-represented functional groups of Candida-induced genes can be classified into the main categories cell death and proliferation, signaling, transcriptional regulation, and cell-cell contacts and intracellular signaling.…”

Section: Discussionmentioning

confidence: 99%

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Müller

Viemann²,

Schmidt

et al. 2007

The Journal of Immunology

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Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-κB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-κB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IκB kinase-2/NF-κB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.

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“…The second implication is that CS addition may contribute to the cell-surface expression of conventional forms of Ii. Both Ii-CS and conventional Ii have been implicated as cell-surface receptors for cell signalling events [9,11,12]. Thus Ii-CS may be essential to both of these functions, either by modulating trafficking of MHCII-Ii complexes or through direct interaction with extracellular ligands.…”

Section: Discussionmentioning

confidence: 99%

“…The resulting N-terminal fragment has been shown to migrate into the nucleus [7], where it stimulates NF-κB (nuclear factor κB) p65/RelA-mediated transcription, resulting in loss of the B-cell maturation block [6,8]. Furthermore, stimulation of surface Ii by MIF (macrophage migration inhibitory factor) binding also appears to induce a signal cascade leading to NF-κB activation, increased expression of Bcl-X L and cell proliferation, suggesting that cell-surface Ii may function as a survival receptor [9].…”

Section: Introductionmentioning

confidence: 99%

The chondroitin sulfate form of invariant chain trimerizes with conventional invariant chain and these complexes are rapidly transported from thetrans-Golgi network to the cell surface

Arneson

Miller

2007

Biochemical Journal

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Targeting of MHCII-invariant chain complexes from the transGolgi network to endosomes is mediated by two di-leucinebased signals present in the cytosolic domain of invariant chain. Generation of this endosomal targeting signal is also dependent on multimerization of the invariant chain cytosolic domain sequences, mediated through assembly of invariant chain into homotrimers. A small subset of invariant chain is modified by the addition of chondroitin sulfate and is expressed on the cell surface in association with MHCII. In the present study, we have followed the biosynthetic pathway and route of intracellular transport of this proteoglycan form of invariant chain. We found that the efficiency of chondroitin sulfate modification can be increased by altering the invariant chain amino acid sequence around Ser-201 to the xylosylation consensus sequence. Our results also indicate that, following sulfation, the proteoglycan form is transported rapidly from the trans-Golgi network to the cell surface and is degraded following internalization into an endocytic compartment. Invariant chain-chondroitin sulfate is present in invariant chain trimers that also include conventional non-proteoglycan forms of invariant chain. These data indicate that invariant chain-chondroitin sulfate-containing complexes are transported rapidly from the trans-Golgi network to the cell surface in spite of the presence of an intact endosomal localization signal. Furthermore, these results suggest that invariant chainchondroitin sulfate may play an important role in the generation of cell-surface pools of invariant chain that can serve as receptors for CD44 and macrophage migration inhibitory factor.

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Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival

Cited by 263 publications

References 43 publications

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

The chondroitin sulfate form of invariant chain trimerizes with conventional invariant chain and these complexes are rapidly transported from thetrans-Golgi network to the cell surface

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