The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways

Bordonaro, Michael; Tewari, Shruti; Atamna, Wafa; Lazarova, Darina L.

doi:10.1016/j.yexcr.2011.03.019

Cited by 26 publications

(27 citation statements)

References 72 publications

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“…Intriguingly, the Dll1 ICD has been shown to induce Wnt reporter activity and upregulate the expression of connective tissue growth factor (CTGF) (Bordonaro et al, 2011). MAML represents another nexus between Notch and Wnt signaling, and, in addition to its role in stabilizing Notch ICD-CSL interactions, MAML has now been shown to bind to both GSK3 (Saint Just Ribeiro et al, 2009) and Notch signaling; sFRPs bind to ADAM10, downregulating its activity and thus inhibiting Notch signaling.…”

Section: Interactions With the Wnt Pathwaymentioning

confidence: 99%

“…In cerebrovascular endothelial cells, SMADs bind to NICD and control the expression of N-cadherin by binding to CSL binding sites in the N-cadherin promoter (Li et al, 2011). Meanwhile, Dll1 ICD binds directly to SMADs and can occupy sequences within the CTGF promoter that contain SMAD binding elements (Bordonaro et al, 2011). During smooth muscle differentiation, TGF downregulates expression of Notch3 but upregulates Hes1 expression (Kennard et al, 2008), whereas in T-cells TGF requires active Notch signaling to induce a regulatory phenotype through Notch ICD/CSL/SMAD-mediated transcription of forkhead box P3 (Foxp3) (Samon et al, 2008).…”

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confidence: 99%

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Notch signaling: simplicity in design, versatility in function

2011

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Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.Key words: Cis-inhibition, Delta-like, Signaling diversity, Jagged, Notch, Notch intracellular domain Introduction Cells need to sense cues from their extracellular environment and integrate this information into appropriate developmental or physiological responses. Although there are a number of mechanisms that relay information from the exterior of the cell to the interior, a relatively small set of highly evolutionarily conserved signaling pathways stand out as playing particularly crucial roles in this transmission of information. In this roster of 'elite' intracellular signaling mechanisms are the Wnt pathway, the sonic hedgehog (Shh) pathway, the bone morphogenetic protein/transforming growth factor  (BMP/TGF) pathway, phosphatidylinositol 3-kinase/thymoma viral proto-oncogene (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and, the subject of this review, the Notch signaling pathway. Each of these pathways converts information about the concentration of extracellular ligands into specific transcriptional responses in the nucleus. In most cases, the signaling mechanism consists of the 'core' signaling pathway, i.e. the minimal set of protein components required for transducing the signal, and a more elaborate set of 'auxiliary' proteins, which, in various ways, impinge upon the core pathway and modify the signal but are not intrinsically necessary for relaying the signal.Among these highly conserved pathways (Gazave et al., 2009;Richards and Degnan, 2009), the Notch signaling pathway scores highly with regard to simplicity in molecular design, as it contains only a small number of core signaling components (Fig. 1). Despite this, Notch signaling affects cell differentiation decisions not only across a wide spectrum of metazoan species, but also across a broad range of cell types in a single organism and at different steps during cell lineage progression. The pleiotropic actions of Notch in different cell types and organs have recently been reviewed and are summarized in Table 1. In keeping with its important role in many cell types, the mutation of Notch genes leads to diseases in various organs and tissues (Table 2). These studies highlight the fact that the Notch pathway must be able to elicit appropriate responses in many spatially and temporally...

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Section: Interactions With the Wnt Pathwaymentioning

confidence: 99%

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confidence: 99%

Notch signaling: simplicity in design, versatility in function

2011

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“…It has been previously shown that like Notch receptors, DSL ligands also undergo proteolytic cleavages by ADAM metalloproteases and γ-secretase following receptor-ligand interaction releasing the L igand I ntra c ellular D omain (LICD) (Bland et al , 2003; Bordonaro et al , 2011; Hiratochi et al , 2007; Ikeuchi and Sisodia, 2003; LaVoie and Selkoe, 2003; Qi et al , 1999; Six et al , 2003; Zolkiewska, 2008). If these endoproteolytic fragments can survive the N-end rule degradation machinery, they would be generated in RBPj msx2LOF , but not in PS msx2LOF .…”

Section: Resultsmentioning

confidence: 99%

The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development

Turkoz

Townsend

Kopan

2016

Journal of Investigative Dermatology

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Ligand-dependent activation, γ-secretase-processed cleavage, and RBPj-mediated downstream transcriptional activities of Notch receptors constitute the “canonical” Notch signaling pathway, which is essential for skin organogenesis. However, in Msx2-Cre mice, keratinocyte-specific deletion of the Rbpj gene in utero produced a significantly milder phenotype than either global Notch or γ-secretase loss. Herein, we investigated the underlying mechanisms for this apparent non-canonical signal using mouse genetics. We found no evidence that ligand back signaling contributed to skin organogenesis. The perdurance of RBPj protein did not establish an epigenetic memory of a canonical signal in the youngest epidermal stem cells, and Notch targets were not de-repressed. We provide evidence that γ-secretase-dependent but RBPj-independent NICD activity operating in the first hair follicles is responsible for a delay in follicular destruction, which results in lower serum TSLP levels, milder B-cell Lymphoproliferative Disease, and improved survival in Msx2-Cre+/tg;Rbpjf/f mice. Minimal amounts of NICD were sufficient for rescue, which was not mediated by transcription, suggesting that NICD is acting through a novel mechanism.

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“…Membrane-bound Notch is physically associated with unphosphorylated β-catenin in stem and colon cancer cells and negatively regulates post-translational accumulation of β-catenin protein by altering the endocytic adaptor protein Numb and lysosomal activity (14). Bordonaro et al revealed that the Notch ligand Delta-like 1 augmented the activity of the Wnt signaling pathway and transcriptionally upregulated the connective tissue growth factor gene and promoted cell growth in colon cancer (15). Zhu et al divided CRC into three transcriptional subtypes, and identified driver networks or pathways for each group.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cell proliferation and tumor growth of colorectal cancer by inhibitors of Wnt and Notch signaling pathways

et al. 2016

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Understanding the role and mechanism of signaling pathways including Notch and Wnt in colorectal carcinogenesis is critical to the development of novel therapeutics. In the present study, we analyzed the cell proliferation, migration, G2/M percentage and the expression of molecules of signaling pathways in HCT-116 cells through the inhibition of Wnt and Notch pathways, and also investigated the effect of inhibitors of Wnt and Notch pathways on tumor growth in a transplantation tumor model. We observed that rDDK-1 (an inhibitor of the Wnt signaling pathway) and LY374973 (an inhibitor of the Notch signaling pathway) synergistically inhibited the proliferation, migration and G2/M percentage of HCT-116 cell lines, and could further synergistically inhibit the tumor volume and weight in the transplantation tumor model. In the cell line and the transplantation tumor model, rDDK-1 and LY374973 further synergistically inhibited the expression level of all detected Wnt and Notch pathway genes. Our results may pave the way for using inhibitors of Wnt and Notch signaling pathways together to treat colorectal cancer.

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The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways

Cited by 26 publications

References 72 publications

Notch signaling: simplicity in design, versatility in function

Notch signaling: simplicity in design, versatility in function

The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development

Inhibition of cell proliferation and tumor growth of colorectal cancer by inhibitors of Wnt and Notch signaling pathways

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