The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism
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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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"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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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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"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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