The Notch amino terminus regulates protein levels and Delta-induced clustering of Drosophila Notch receptors

Bardot, Boris; Mok, Lee-Peng; Thayer, Tristan; Ahimou, François; Wesley, Cedric S.

doi:10.1016/j.yexcr.2004.10.030

Cited by 28 publications

(34 citation statements)

References 81 publications

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“…The restricted distribution of molecules at the plasma membrane, the observation of receptor clustering in signaling complexes (Ahimou et al, 2004; Bardot et al, 2005; Nichols et al, 2007) and the presence of an additional weak dimerization interface within the intracellular ankyrin repeat domain of Notch (Allgood and Barrick, 2011; Nam et al, 2007; Nam et al, 2006) also point toward a potential role for dimerization in modulating signal transduction. Consistent with this idea, reporter gene assays suggest that autoinhibition is partially disrupted by mutations that destabilize the dimerization interface.…”

Section: Discussionmentioning

confidence: 99%

Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region

Choi

et al. 2015

Structure

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Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LNR modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors.

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Section: Discussionmentioning

confidence: 99%

Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region

Choi

et al. 2015

Structure

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“…Furthermore, it is possible that increasing density of ligand in these cultures increased the possibility of interaction with and activation of Notch receptors. However, although dimerization has not been shown to contribute to receptor activation, there is emerging evidence that receptor-ligand interaction induces clustering of Notch receptors with resultant effects on the accumulation and internalization of the receptor, 35 but the contribution of clustering to Notch signaling remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells

Delaney

Varnum‐Finney

Aoyama

et al. 2005

Blood

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IntroductionThe widespread expression of Notch family members by hematopoietic cells, including stem cells, has led to speculation about their role in hematopoiesis. A critical role for Notch signaling in T versus B cell-fate decisions has been established in vivo with gain-and loss-of-function studies. 1-3 Despite profound effects on lymphoid cell fates, these studies have failed to identify significant effects on myeloid differentiation. However, in contrast to these in vivo studies, in vitro studies in which the constitutively active intracellular domain of Notch1 was overexpressed did reveal inhibition of myeloid differentiation and enhanced generation of precursor cells in addition to promotion of early T-cell differentiation, indicating a potential role of Notch signaling on multipotent precursor cells. [4][5][6][7] To exploit Notch signaling as a means of directing desired cell-fate outcomes or generating precursor cells from nontransduced stem cells, soluble or cell-expressed Notch ligands have been used by a number of laboratories. Initial studies met with only modest success, resulting in only a few-fold increase in progenitor cell number, 4,5,[7][8][9][10][11][12] but our more recent studies using an engineered Notch ligand Delta1 in immobilized form demonstrated profound effects on murine precursors with a multilog increase in the number of Sca-1 ϩ c-kit ϩ precursors with short-term lymphoid and myeloid repopulating ability. 7 Based on these findings, we examined Notch signaling in human cord blood precursors because inadequate stem cell numbers in cord blood grafts have been associated with significantly delayed engraftment and, as a result, increased early transplant-related mortality from infection, thereby limiting the use of cord blood for hematopoietic cell transplantation (HCT) in adults and larger children. Our studies demonstrated an increase in early human hematopoietic reconstitution in NOD/SCID mice, indicating potential clinical importance in overcoming the delayed engraftment in umbilical cord blood transplants. 5 We investigated whether quantitative differences in ligandinduced activation of Notch signaling could be the basis for the reported variability with Notch activation and cell fate outcomes of hematopoietic precursors and whether such quantitative differences might determine whether precursors self-renew or adopt a lymphoid cell fate. The importance of quantitative aspects of Notch signaling has been shown in Drosophila where different functions of Notch can require different thresholds of signaling. For example, Notch haploinsufficiency suffices to perform most functions of Notch indistinguishably from wild type, but causes improper specification of the dorsoventral margin of the wing, giving rise to the eponymous "notched wing" phenotype. 13,14 In mammals, a reduction in Notch1 gene dosage in developing T cells favors the ␥␦ T-cell fate over the ␣␤ T-cell fate, 15 and a dose-dependent effect of Delta1 on the determination of type 1 helper T cell (Th1) versus Th2 cell-fate dec...

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“…Schneider 2 (S2) cells express neither Notch nor Delta but can be made to express one or the other protein using transgenes. S2-Notch cells treated with S2-Delta cells recapitulate all known aspects of Notch function [5], [6], [8], [9], [12], [16], [19], [25]–[27], [35]. Experiments with these cells show that F-actin accumulates near the Notch receptor clusters that form at S2-Notch cell surfaces in contact with S2-Delta cells.…”

Section: Introductionmentioning

confidence: 99%

Notch and PKC Are Involved in Formation of the Lateral Region of the Dorso-Ventral Axis in Drosophila Embryos

et al. 2013

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The Notch gene encodes an evolutionarily conserved cell surface receptor that generates regulatory signals based on interactions between neighboring cells. In Drosophila embryos it is normally expressed at a low level due to strong negative regulation. When this negative regulation is abrogated neurogenesis in the ventral region is suppressed, the development of lateral epidermis is severely disrupted, and the dorsal aminoserosa is expanded. Of these phenotypes only the anti-neurogenic phenotype could be linked to excess canonical Notch signaling. The other phenotypes were linked to high levels of Notch protein expression at the surface of cells in the lateral regions indicating that a non-canonical Notch signaling activity normally functions in these regions. Results of our studies reported here provide evidence. They show that Notch activities are inextricably linked to that of Pkc98E, the homolog of mammalian PKCδ. Notch and Pkc98E up-regulate the levels of the phosphorylated form of IκBCactus, a negative regulator of Toll signaling, and Mothers against dpp (MAD), an effector of Dpp signaling. Our data suggest that in the lateral regions of the Drosophila embryos Notch activity, in conjunction with Pkc98E activity, is used to form the slopes of the opposing gradients of Toll and Dpp signaling that specify cell fates along the dorso-ventral axis.

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The Notch amino terminus regulates protein levels and Delta-induced clustering of Drosophila Notch receptors

Cited by 28 publications

References 81 publications

Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region

Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells

Notch and PKC Are Involved in Formation of the Lateral Region of the Dorso-Ventral Axis in Drosophila Embryos

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