Ubiquitinations in the Notch Signaling Pathway

Moretti, Julien; Brou, Christel

doi:10.3390/ijms14036359

Cited by 60 publications

(58 citation statements)

References 122 publications

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“…Thus, by manipulating the ubiquitin-proteasome pathway, HCMV is able to create an environment that will facilitate viral replication (42). Although it was previously reported that the proteasome is involved in the degradation of NICD1 and Jag1, these results were observed in cells expressing NICD1 and Jag1 exogenously (43,45,(63)(64)(65)(66). In this study, we further demonstrated that endogenous NICD1 and Jag1 proteins are also subjected to proteasomal degradation in human NPCs and that HCMV manipulates the ubiquitin-proteasome, enhancing the degradation of NICD1 and Jag1 proteins.…”

Section: Discussioncontrasting

confidence: 50%

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Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Liu

Yang

et al. 2015

J Virol

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Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.

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Section: Discussioncontrasting

confidence: 50%

“…The E3 ligases of Numb, Deltex1, SEL-10, and Neural1 have previously been shown to be involved in the regulation of Notch receptors or ligands via the proteasome (43,45,63,64,66). We found that RNA levels of Numb, Deltex1, SEL-10, and Neural1 NPCs.…”

Section: Discussionmentioning

confidence: 51%

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Liu

Yang

et al. 2015

J Virol

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“…E3 ubiquitin ligases are the only enzymes in the ubiquitination process to be specific for the substrate. 29,73 Notch-ICD contains a canonical PEST sequence, which is associated with short lifetime molecules 29 since it is associated with phosphorylation and ubiquitination. 74 The present study identifies a novel mechanism for Int3 regulation of mammary gland development through the direct effects of GSK3b.…”

Section: Discussionmentioning

confidence: 99%

“…Notch receptors and their ligands are potential substrates for ubiquitin addition by E3 ligases. [27][28][29] It has been demonstrated that Notch-ICD is rapidly polyubiquitinated and degraded through the proteasomal pathway, and the E3 ubiquitin ligase accounting for these modifications is Fbw7/Sel-10. [30][31][32] To elucidate the mechanism by which Gleevec inhibits Notch signaling, we established in vitro and in vivo systems using cell lines and transgenic mice.…”

Section: 2mentioning

confidence: 99%

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Original Research: Featured Article: Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development

Callahan

Chestnut

Raafat

2016

Exp Biol Med (Maywood)

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Wap-Int3 transgenic females expressing the Notch4 intracellular domain (designated Int3) from the whey acidic protein promoter exhibit two phenotypes in the mammary gland: blockage of lobuloalveolar development and lactation, and tumor development with 100% penetrance. Previously, we have shown that treatment of Wap-Int3 tumor bearing mice with Imatinib mesylate (Gleevec) is associated with complete regression of the tumor. In the present study, we show that treatment of Wap-Int3 mice during day 1 through day 6 of pregnancy with Gleevec leads to the restoration of their lobuloalveolar development and ability to lactate in subsequent pregnancies in absence of Gleevec treatment. In addition, these mice do not develop mammary tumors. We investigated the mechanism for Gleevec regulation of Notch signaling and found that Gleevec treatment results in a loss of Int3 protein but not of Int3 mRNA in HC11 mouse mammary epithelial cells expressing Int3. The addition of MG-132, a proteasome inhibitor, shows increased ubiquitination of Int3 in the presence of Gleevec. Thus, Gleevec affects the stability of Int3 by promoting the degradation of Int3 via E3 ubiquitin ligases targeting it for the proteasome degradation. Gleevec is a tyrosine kinase inhibitor that acts on c-Kit and PDGFR. Therefore, we investigated the downstream substrate kinase GSK3b to ascertain the possible role that this kinase might play in the stability of Int3. Data show that Gleevec degradation of Int3 is GSK3b dependent. We have expanded our study of the effects Gleevec has on tumorigenesis of other oncogenes. We have found that anchorage-independent growth of HC11-c-Myc cells as well as tumor growth in nude mice is inhibited by Gleevec treatment. As with Int3, Gleevec treatment appears to destabilize the c-Myc protein but not mRNA. These results indicate that Gleevec could be a potential therapeutic drug for patients bearing Notch4 and/or c-Myc positive breast carcinomas.

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Macroautophagy Regulates Nuclear NOTCH1 Activity Through Multiple p62 Binding Sites

et al. 2018

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NOTCH1 is the prototype of the NOTCH family of single-pass transmembrane receptors and regulates many basic processes during embryonic development and human pathogenesis. In core to NOTCH1 activation are proteolytic cleavages that release its intracellular domain (NICD1), which in turn translocates to the nucleus to regulate gene transcription. Macroautophagy (hereafter autophagy) has been shown to promote the degradation of NOTCH1, but the underlying mechanisms remain elusive. Here, we show that autophagy promotes the degradation of NOTCH1 by p62-dependent binding between NICD1 and LC3, a component of the autophagosomes that execute autophagy. Strikingly, deleting any of the structural NICD1 domains fails to block the degradation of NICD1 by autophagy, and p62 binds to almost all these domains independently, indicating that p62 binds to multiple sites on NICD1 to promote its degradation. Intriguingly, inhibition of autophagy induces the accumulation of NICD1 in not only the cytoplasm but also the nucleus and increases the transcriptional activity of NICD1, and such regulation of nuclear NICD1 by autophagy is unique to NICD1 and not observed for all other NICDs (NICD2-4). Collectively, our results suggest that autophagy tightly controls nuclear NOTCH1 activity through multiple p62 binding sites, and that modulating autophagy activity may be useful for treating NOTCH1 related human diseases. © 2018 IUBMB Life, 70(10):985-994, 2018.

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Ubiquitinations in the Notch Signaling Pathway

Cited by 60 publications

References 122 publications

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Original Research: Featured Article: Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development

Macroautophagy Regulates Nuclear NOTCH1 Activity Through Multiple p62 Binding Sites

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