Ligand-Induced Signaling in the Absence of Furin Processing of Notch1

diSibio, Guy; Miyamoto, Alison; Denault, Jean‐Bernard; Leduc, Richard; Weinmaster, Gerry

doi:10.1006/dbio.2000.9992

Cited by 117 publications

(86 citation statements)

References 24 publications

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“…These findings raise questions about the specificity of these inhibitors in the complex cell-signaling system. Furthermore, ␥-secretase inhibitors do not differentiate between the Notch ligands involved in regulation of T cell functions, and a previous report showed that Notch signaling could be induced independently of ␥-secretase in mutant forms of Notch (43) suggesting that the ␥-secretase inhibitor may block only a part of Notch's functions. Significant genetic evidence of the existence of CSL-independent Notch signaling has been shown although the molecular components of this pathway and its downstream targets remain largely unknown (44).…”

Section: Discussionmentioning

confidence: 97%

Jagged1 and Delta1 Differentially Regulate the Outcome of Experimental Autoimmune Encephalomyelitis

Elyaman

Bradshaw

Wang

et al. 2007

The Journal of Immunology

113

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Notch signaling plays an important role during T cell development in the thymus and in T cell activation but the role of Notch in autoimmunity is not clear. We investigated the role of Jagged1 and Delta1 in experimental autoimmune encephalomyelitis. During experimental autoimmune encephalomyelitis, Delta1 expression is up-regulated on dendritic cells and B cells after priming while Jagged1 is up-regulated only on dendritic cells. Administration of anti-Jagged1 Ab exacerbated clinical disease while that of anti-Delta1 Ab reduced the severity of the clinical disease. In contrast, administration of Jagged1-Fc protected from disease, that of Delta1-Fc exacerbated disease. Treatment with Jagged1-Fc was associated with increased IL-10-producing Ag-specific cells in the CNS, while anti-Jagged1 decreased the frequency of IL-10-producing cells. Treatment with Delta1-Fc increased Th1 cells in the CNS, while anti-Delta-1 decreased the frequency of Th1 cells. Manipulation of Delta1 or Jagged1 had no effect on the frequency of Th17 cells or FoxP3+ cells. Moreover, Jagged1 may play a role in CNS homeostasis because murine astrocytes specifically express Jagged1 that is up-regulated by TGF-β, whereas IFN-γ, TNF-α, and IL-17 decrease Jagged1 expression. Our study provides novel data about differential roles of Notch ligands in regulating inflammation in the periphery as well as in the CNS.

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Section: Discussionmentioning

confidence: 97%

Jagged1 and Delta1 Differentially Regulate the Outcome of Experimental Autoimmune Encephalomyelitis

Elyaman

Bradshaw

Wang

et al. 2007

The Journal of Immunology

113

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“…By blocking the proteolytic release of N-IC, these compounds block the classical CSL-dependent Notch signaling pathway. Importantly, however, mutant forms of Notch which are resistant to furin cleavage in the secretory pathway, and therefore are resistant to subsequent ␥ secretase cleavage, are still able to inhibit myogenesis in a ligand-dependent but CSL-independent manner (30). This demonstrates the existence of signaling events that are cleavage ϩ T cell cytokine responses.…”

Section: Discussionmentioning

confidence: 99%

Small Interfering RNA-Mediated Knockdown of Notch Ligands in Primary CD4+ T Cells and Dendritic Cells Enhances Cytokine Production

Stallwood¹,

Briend²,

Ray³

et al. 2006

The Journal of Immunology

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The key interaction in the adaptive immune system’s response to pathogenic challenge occurs at the interface between APCs and T cells. Families of costimulatory and coinhibitory molecules function in association with the cytokine microenvironment to orchestrate appropriate T cell activation programs. Recent data have demonstrated that the Notch receptor and its ligands also function at the APC:T interface. In this study, we describe synthetic small interfering RNA (siRNA) sequences targeting the human Notch ligands Delta1, Jagged1 and Jagged2. Transfection of these siRNAs into human primary CD4+ T cells and monocyte-derived dendritic cells leads to knockdown of endogenous Notch ligand message. Knockdown of any one of these three Notch ligands in dendritic cells enhanced IFN-γ production from allogeneic CD4+ T cells in MLR. In contrast, Delta1 knockdown in CD4+ T cells selectively enhanced production of IFN-γ, IL-2, and IL-5 in response to polyclonal stimulation, while Jagged1 or Jagged2 knockdown had no effect. Strikingly, blockade of Notch cleavage with a γ secretase inhibitor failed to affect cytokine production in this system, implying that Delta1 can influence cytokine production via a Notch cleavage-independent mechanism. These data show for the first time that the Notch pathway can be targeted by siRNA, and that its antagonism may be a unique therapeutic opportunity for immune enhancement.

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“…Cell Surface Biotinylation-Isolation of cell surface proteins was performed essentially as previously described with minor modifications (20). Briefly, naive or differentiated PC12 cells were rinsed 3 times with ice-cold PBS and then incubated with either PBS alone (non-biotinylated controls) or PBS containing 0.5 mg/ml Sulfo-NHS-LC-Biotin (Pierce) for 2 h at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Persistent TrkA Activity Is Necessary to Maintain Transcription in Neuronally Differentiated PC12 Cells

Chang

Mellon

Schanen

et al. 2003

Journal of Biological Chemistry

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Neurotrophins are required for the differentiation and survival of several different neuronal subpopulations in the developing nervous system. The PC12 cell line responds to nerve growth factor (NGF) by withdrawing from the cell cycle and acquiring a sympathetic neuronlike phenotype. Previous studies have shown that the activation kinetics of the NGF receptor, TrkA, and downstream protein kinases appear rapid and seemingly transient after NGF treatment of naive PC12 cells. However, maintenance of the neuronal phenotype and survival of differentiated PC12 cells under serum-free conditions require constant NGF exposure. In this study we have addressed the mechanisms that NGF uses to maintain neuronal PC12 cells. We show that TrkA remains phosphorylated at a basal level throughout differentiation of the PC12 cells. The phospho-TrkA levels in the differentiated PC12 cells were diminished by both complete NGF withdrawal and pharmacological inhibition of Trk kinase activity. Intracellular sequestration of the majority of TrkA molecules (both phosphorylated and nonphosphorylated TrkA) and persistent dephosphorylation of the small pool of cell surface TrkA renders the persistent phospho-TrkA signal in the differentiated PC12 cells resistant to partial NGF withdrawal as well as exposure to additional NGF. NGF regulated both extracellular-regulated kinases 1/2 and Akt activity in the differentiated PC12 cells via sustained TrkA activity. Moreover, analysis of transcription using activating protein 1-, serum response element-, and cyclic AMP response element-Luc reporter constructs showed that NGF regulated these promoters through TrkA activity in differentiated PC12 cells. Interestingly, the initial response of the cyclic AMP response element promoter to NGF was delayed, becoming Trk-dependent well beyond the peaks in TrkA and downstream protein kinase signal transduction.During development, nerve growth factor (NGF) 1 has profound effects on the differentiation and survival of subsets of neurons in the peripheral and central nervous systems (1). These effects are largely mediated through activation of the TrkA receptor, which initiates a cascade of signaling events that includes activation of several downstream protein kinases and transcription factors (2). These early events are thought to generate the long term changes in gene expression needed for acquisition of a mature neuronal phenotype. Mature or adult neurons are also exposed to and responsive to neurotrophins like NGF, but their biological responses may be quite distinct from those of an immature neuron. For example, developing nociceptive neurons in the dorsal root ganglion require NGF for survival (3). NGF alters neurite outgrowth, gene induction, and the responsiveness of adult nociceptive neurons to some stimuli, but it is apparently not necessary for their survival (4 -6). Much effort has been devoted toward understanding how NGF and other neurotrophins bring about their biological effects in both the developing and adult nervous systems. Most studies of ne...

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Ligand-Induced Signaling in the Absence of Furin Processing of Notch1

Cited by 117 publications

References 24 publications

Jagged1 and Delta1 Differentially Regulate the Outcome of Experimental Autoimmune Encephalomyelitis

Jagged1 and Delta1 Differentially Regulate the Outcome of Experimental Autoimmune Encephalomyelitis

Small Interfering RNA-Mediated Knockdown of Notch Ligands in Primary CD4+ T Cells and Dendritic Cells Enhances Cytokine Production

Persistent TrkA Activity Is Necessary to Maintain Transcription in Neuronally Differentiated PC12 Cells

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