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Journal ArticleDOI

The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

17 Apr 2009-Cell (NIH Public Access)-Vol. 137, Iss: 2, pp 216-233
TL;DR: This Review highlights recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
About: This article is published in Cell.The article was published on 2009-04-17 and is currently open access. It has received 3120 citations till now. The article focuses on the topics: Notch signaling pathway & Notch 1.
Citations
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Journal ArticleDOI
TL;DR: This review summarizes the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.
Abstract: CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

2,978 citations

Journal ArticleDOI
26 Jun 2009-Science
TL;DR: Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
Abstract: Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.

2,446 citations

Journal ArticleDOI
26 Aug 2011-Science
TL;DR: To explore the genetic origins of head and neck squamous cell carcinoma, whole-exome sequencing and gene copy number analyses were used to study 32 primary tumors and identified mutations in FBXW7 and NotCH1, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

1,613 citations

Journal ArticleDOI
TL;DR: New evidence suggests that miRNAs affect the responsiveness of cells to signalling molecules such as transforming growth factor-β, WNT, Notch and epidermal growth factor, which serves as nodes of signalling networks that ensure homeostasis and regulate cancer, metastasis, fibrosis and stem cell biology.
Abstract: MicroRNAs (miRNAs) are integral elements in the post-transcriptional control of gene expression. After the identification of hundreds of miRNAs, the challenge is now to understand their specific biological function. Signalling pathways are ideal candidates for miRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Indeed, emerging evidence suggests that miRNAs affect the responsiveness of cells to signalling molecules such as transforming growth factor-beta, WNT, Notch and epidermal growth factor. As such, miRNAs serve as nodes of signalling networks that ensure homeostasis and regulate cancer, metastasis, fibrosis and stem cell biology.

1,207 citations

Journal ArticleDOI
TL;DR: Sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.
Abstract: All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

875 citations


Cites background from "The Canonical Notch Signaling Pathw..."

  • ...Given that the ligand-binding domain of Notch is in close proximity to the protective Lin12–Notch repeat (LNR) modules, this coincides with data showing that ligand-binding confers sufficient force to peel away the LNR modules, providing the 'lift' that exposes the metalloprotease cleavage site where the 'cut' required for activation occur...

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References
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Journal ArticleDOI
08 Oct 2004-Science
TL;DR: These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Abstract: Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

2,700 citations


"The Canonical Notch Signaling Pathw..." refers background in this paper

  • ...“Leaky” Notch signaling occurs when point mutations (Weng et al., 2004) or viral integration (Girard et al., 1996) disrupt the negative regulatory region, causing T cell acute lymphoblastic leukemia in humans and lymphomas in mice, respectively....

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  • ...Highlighting the importance of NICD turnover is the observation that deletion of the Notch receptor C-terminal or PEST domain, or mutations that stabilize NICD, can cause T cell acute lymphoblastic leukemia in humans (Weng et al., 2004)....

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  • ...“Leaky” Notch signaling occurs when point mutations (Weng et al., 2004) or viral integration (Girard et al....

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  • ...Notch signaling has emerged as a specific therapeutic target for T cell acute lymphoblastic leukemia (Weng et al., 2004) and colon cancer (van Es et al....

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  • ...Notch signaling has emerged as a specific therapeutic target for T cell acute lymphoblastic leukemia (Weng et al., 2004) and colon cancer (van Es et al., 2005), as well as a potential target in the effort to curb tumor angiogenesis (Noguera-Troise et al., 2006; Ridgway et al., 2006)....

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Journal ArticleDOI
TL;DR: Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
Abstract: A small number of signalling pathways are used iteratively to regulate cell fates, cell proliferation and cell death in development. Notch is the receptor in one such pathway, and is unusual in that most of its ligands are also transmembrane proteins; therefore signalling is restricted to neighbouring cells. Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.

2,450 citations


"The Canonical Notch Signaling Pathw..." refers background in this paper

  • ...…although the CSL protein RBPjκ can form complexes with many ubiquitous corepressor proteins, such as CIR, FLH1C/KyoT2, and NCoR/SMRT (reviewed in Bray, 2006), it is SHARP/MINT/SPEN that has emerged as the critical repressor of Notch target genes in vivo (Oswald et al., 2005; Tsuji et al.,…...

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  • ..., and Bray, S. (2001). A model Notch response element detects Suppressor of Hairless-dependent molecular switch....

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  • ...The nuclear milieu that exists before the arrival of NICD will dictate which targets are available to CSL and thus can be activated by Notch (reviewed in Bray, 2006)....

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  • ...For example, several E3 ubiquitin ligases—Deltex, Nedd4, Su(Dx)/ Itch, Cbl—can direct Notch receptor trafficking toward lysosomal degradation or toward recycling, thereby impacting receptor half life (reviewed in Bray, 2006; Le Borgne, 2006; Nichols et al., 2007b)....

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  • ...It is now well established that Notch receptor activation is mediated by a sequence of proteolytic events (Figures 1 and 2A) (reviewed in Bray, 2006)....

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Journal ArticleDOI
13 Nov 1998-Science
TL;DR: The phenotype of mice lacking TACE suggests an essential role for soluble TGFalpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.
Abstract: The ectodomains of numerous proteins are released from cells by proteolysis to yield soluble intercellular regulators. The responsible protease, tumor necrosis factor-alpha converting enzyme (TACE), has been identified only in the case when tumor necrosis factor-alpha (TNFalpha) is released. Analyses of cells lacking this metalloproteinase-disintegrin revealed an expanded role for TACE in the processing of other cell surface proteins, including a TNF receptor, the L-selectin adhesion molecule, and transforming growth factor-alpha (TGFalpha). The phenotype of mice lacking TACE suggests an essential role for soluble TGFalpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.

1,627 citations

Journal ArticleDOI
28 May 1998-Nature
TL;DR: It is shown that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL.
Abstract: Notch proteins are ligand-activated transmembrane receptors involved in cell-fate selection throughout development1,2,3. No known enzymatic activity is contained within Notch and the molecular mechanism by which it transduces signals across the cell membrane is poorly understood. In many instances, Notch activation results in transcriptional changes in the nucleus through an association with members of the CSL family of DNA-binding proteins (where CSL stands for CBF1, Su(H), Lag-1)1,2,3,4. As Notch is located in the plasma membrane and CSL is a nuclear protein, two models have been proposed to explain how they interact (Fig. 1) . The first suggests that the two interact transiently at the membrane1,5,6,7. The second postulates that Notch is cleaved by a protease, enabling the cleaved fragment to enter the nucleus6,8,9,10,11,12,13,14. Here we show that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL. Very small amounts of NICD are active, explaining why it is hard to detect in the nucleus in vivo. We also show that it is ligand binding that induces release of NICD.

1,625 citations


"The Canonical Notch Signaling Pathw..." refers background in this paper

  • ...More recently, mass spectrometric analysis of cleavage products from an in vitro assay using NEXT-like substrates identified NICD variants with diverse N termini (NICD-V starting with V1744; NICD-L molecules starting with lysine 1745 or 1746; NICD-S starting with serine 1747) (Figure 2A) (Tagami et al., 2008)....

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  • ...At the plasma membrane, the bond between G1743 and V1744 is preferentially cleaved to generate the stable NICD-V species....

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  • ...Like V1744G, the K1749R substitution caused a shift in scissile bond preference, producing labile NICD species instead of NICD-V and thus leading to a loss of Notch activity....

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  • ...Immunoprecipitation and Edman sequencing of mouse Notch1 C-terminal fragments identified a single NICD species starting at valine 1744 (V1744) (Schroeter et al., 1998)....

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  • ...NICD species starting at valine 1744 (V1744) (Schroeter et al., 1998)....

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Journal ArticleDOI
16 Jun 2005-Nature
TL;DR: This work shows a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J and indicates that γ-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.
Abstract: The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt-villus axis. Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J. We obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that gamma-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.

1,555 citations