Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling

Sun, Youping; Lowther, William; Kato, Katsuaki; Bianco, Caterina; Kenney, Nicholas; Strizzi, Luigi; Raafat, Dina; Hirota, Morihisa; Khan, Nazir Ahmad; Bargo, Sharon; Jones, Brenda; Salomon, David; Callahan, Robert

doi:10.1038/sj.onc.1208528

Cited by 87 publications

(66 citation statements)

References 52 publications

(66 reference statements)

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“…Although we confirmed the physical interaction between NICD and Smad3 by co-immunoprecipitation in transiently transfected 293T cells (Fig. 5C) (18, 21), whether the stabilization of Smad3 by Notch is through physical interaction between Smad3 and NICD remains to be further investigated, because NICD has also been shown to interact with Smad1 and Smad2 (21,35).…”

Section: Inhibition Of Notch Activity Reduces Smad3 Expression In Thementioning

confidence: 65%

Differential Regulation of Transforming Growth Factor β Signaling Pathways by Notch in Human Endothelial Cells

Chang

et al. 2009

Journal of Biological Chemistry

103

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Notch and transforming growth factor ␤ (TGF␤) play critical roles in endothelial-to-mesenchymal transition (EndMT), a process that is essential for heart development. Previously, we have shown that Notch and TGF␤ signaling synergistically induce Snail expression in endothelial cells, which is required for EndMT in cardiac cushion morphogenesis. Here, we report that Notch activation modulates TGF␤ signaling pathways in a receptor-activated Smad (R-Smad)-specific manner. Notch activation inhibits TGF␤/Smad1 and TGF␤/Smad2 signaling pathways by decreasing the expression of Smad1 and Smad2 and their target genes. In contrast, Notch increases SMAD3 mRNA expression and protein half-life and regulates the expression of TGF␤/Smad3 target genes in a gene-specific manner. Inhibition of Notch in the cardiac cushion of mouse embryonic hearts reduces Smad3 expression. Notch and TGF␤ synergistically upregulate a subset of genes by recruiting Smad3 to both Smad and CSL binding sites and cooperatively inducing histone H4 acetylation. This is the first evidence that Notch activation affects R-Smad expression and that cooperative induction of histone acetylation at specific promoters underlies the selective synergy between Notch and TGF␤ signaling pathways.

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Section: Inhibition Of Notch Activity Reduces Smad3 Expression In Thementioning

confidence: 65%

Differential Regulation of Transforming Growth Factor β Signaling Pathways by Notch in Human Endothelial Cells

Chang

et al. 2009

Journal of Biological Chemistry

103

View full text Add to dashboard Cite

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“…Alternatively, NOTCH activation could interfere with the auto-regulatory loop that controls Nodal expression in the early epiblast (Adachi et al, 1999;Norris et al, 2002;Norris and Robertson, 1999). NICD has been shown to antagonise TGFβ signalling in various cell types via direct binding to SMAD3 or its co-activators (Carlson et al, 2008;Masuda et al, 2005;Sun et al, 2005). A similar antagonistic activity of NICD on SMAD effectors could dampen the NODAL pathway leading in turn to reduced Nodal expression in N1ICD epi embryos.…”

Section: Discussionmentioning

confidence: 99%

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

et al. 2015

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NOTCH signalling is an evolutionarily conserved pathway involved in intercellular communication essential for cell fate choices during development. Although dispensable for early aspects of mouse development, canonical RBPJ-dependent NOTCH signalling has been shown to influence lineage commitment during embryonic stem cell (ESC) differentiation. NOTCH activation in ESCs promotes the acquisition of a neural fate, whereas its suppression favours their differentiation into cardiomyocytes. This suggests that NOTCH signalling is implicated in the acquisition of distinct embryonic fates at early stages of mammalian development. In order to investigate in vivo such a role for NOTCH signalling in shaping cell fate specification, we use genetic approaches to constitutively activate the NOTCH pathway in the mouse embryo. Early embryonic development, including the establishment of anterior-posterior polarity, is not perturbed by forced NOTCH activation. By contrast, widespread NOTCH activity in the epiblast triggers dramatic gastrulation defects. These are fully rescued in a RBPJ-deficient background. Epiblast-specific NOTCH activation induces acquisition of neurectoderm identity and disrupts the formation of specific mesodermal precursors including the derivatives of the anterior primitive streak, the mouse organiser. In addition, we show that forced NOTCH activation results in misregulation of NODAL signalling, a major determinant of early embryonic patterning. Our study reveals a previously unidentified role for canonical NOTCH signalling during mammalian gastrulation. It also exemplifies how in vivo studies can shed light on the mechanisms underlying cell fate specification during in vitro directed differentiation.

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“…MAPK/ERK signaling is active in undifferentiated human ES cells and is down-regulated upon differentiation [48]. These signaling pathways may thus constitute a complex signaling network actively maintaining ES cell pluripotency [49][50][51][52][53][54][55][56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

et al. 2008

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npg Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their overexpression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signaling network necessary for ES cell pluripotency. However, systemic analysis of the signaling pathways regulated by Yamanaka factors has not yet been fully described. In this study, we identified the target promoters of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin immunoprecipitation)-on-chip in E14.1 mouse ES cells, and we found that these four factors co-occupied 58 promoters. Interestingly, when Oct4 and Sox2 were analyzed as core factors, Klf4 functioned to enhance the core factors for development regulation, whereas c-Myc seemed to play a distinct role in regulating metabolism. The pathway analysis revealed that Yamanaka factors collectively regulate a developmental signaling network composed of 16 developmental signaling pathways, nine of which represent earlier unknown pathways in ES cells, including apoptosis and cellcycle pathways. We further analyzed data from a recent study examining Yamanaka factors in mouse ES cells. Interestingly, this analysis also revealed 16 developmental signaling pathways, of which 14 pathways overlap with the ones revealed by this study, despite that the target genes and the signaling pathways regulated by each individual Yamanaka factor differ significantly between these two datasets. We suggest that Yamanaka factors critically regulate a developmental signaling network composed of approximately a dozen crucial developmental signaling pathways to maintain the pluripotency of ES cells and probably also to induce pluripotent stem cells.

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Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling

Cited by 87 publications

References 52 publications

Differential Regulation of Transforming Growth Factor β Signaling Pathways by Notch in Human Endothelial Cells

Differential Regulation of Transforming Growth Factor β Signaling Pathways by Notch in Human Endothelial Cells

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

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