Regulation of Notch signaling by E3 ubiquitin ligases

Dutta, Debdeep; Sharma, Vartika; Mutsuddi, Mousumi; Mukherjee, Ashim

doi:10.1111/febs.15792

Cited by 29 publications

(14 citation statements)

References 159 publications

(268 reference statements)

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“…In this study, although we could not address the role of endogenous D1ICD in Dll1 function, which activates Notch signaling in neighboring cells, the intracellular domain of Notch ligands is ubiquitinated for their processing, which is required for the maintenance and activation of Notch signaling in neighboring cells (Dutta et al, 2021). Thus, D1ICD may regulate Notch signaling not only in a cell-autonomous manner but also in a non-cell-autonomous manner.…”

Section: Discussionmentioning

confidence: 88%

Cleaved Delta like 1 intracellular domain regulates neural development via Notch signal-dependent and -independent pathways

et al. 2021

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Notch-Delta signaling regulates many developmental processes, including tissue homeostasis, and maintenance of stem cells. Upon interaction of juxtaposed cells via Notch and Delta proteins, intracellular domains of both transmembrane proteins are cleaved and translocate to the nucleus. Notch intracellular domain activates target gene expression; however, the role of the Delta intracellular domain remains elusive. Here, we show the biological function of Delta like 1 intracellular domain (D1ICD) by modulating its production. We find the sustained production of D1ICD abrogates cell proliferation but enhances neurogenesis in the developing dorsal root ganglia (DRG), whereas inhibition of D1ICD production promotes cell proliferation and gliogenesis. D1ICD acts as an integral component of lateral inhibition mechanism by inhibiting Notch activity. In addition, D1ICD promotes neurogenesis through a Notch signaling independent manner. We show that D1ICD binds to Erk1/2 in neural crest stem cells, and inhibits the phosphorylation of Erk1/2. In summary, our results indicate that D1ICD regulates DRG development via modulating not only Notch signaling but also the MAP kinase pathway.

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Section: Discussionmentioning

confidence: 88%

Cleaved Delta like 1 intracellular domain regulates neural development via Notch signal-dependent and -independent pathways

et al. 2021

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“…GSIs are wellknown pan-Notch inhibitors that show serious adverse effects in clinical trials, such as gastrointestinal toxicity. 79 In addition, formation of the NICD-CSL-MAML complex and ubiquitination of Notch receptors are both key processes of Notch signaling, 2,[80][81][82] and blocking these aspects may not only affect Notch4, but also Notch1-3 signaling pathways. Thus, the efficiency and safety of these treatment methods should be further evaluated in future studies.…”

Section: Blocking Notch4 Signal Transductionmentioning

confidence: 99%

Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Xiu¹,

Zeng²,

Shan³

et al. 2021

CMAR

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The dysregulation of Notch signaling is found in many cancers and is closely related to cancer progression. As an important Notch receptor, abnormal Notch4 expression affects several tumor-cell behaviors, including stemness, the epithelial-mesenchymal transition, radio/chemoresistance and angiogenesis. In order to inhibit the oncogenic effects of Notch4 activation, several methods for targeting Notch4 signaling have been proposed. In this review, we summarize the known molecular mechanisms through which Notch4 affects cancer progression. Finally, we discuss potential Notch4-targeting therapeutic strategies as a reference for future research.

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“…We also observed the modulation of key proteins involved in the Notch pathway, such as: JAG2 (putative Notch ligand, only in infected cells), AAK1 and NEDD4 (both being under-expressed). NEDD4 E3 ligase is an important regulator of Notch signaling, and it ubiquitinates Notch and regulates Notch expression at the cell surface, causing its removal from the cell surface and targeting it for lysosomal degradation [49]. Nicastrin (NCSTN), that plays a role in Notch and Wnt signaling cascades, was found to be overexpressed in infected cells.…”

Section: Manipulation Of the Host Immune Response And Signaling Pathwaysmentioning

confidence: 99%

Revisiting Ehrlichia ruminantium Replication Cycle Using Proteomics: The Host and the Bacterium Perspectives

et al. 2021

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The Rickettsiales Ehrlichia ruminantium, the causal agent of the fatal tick-borne disease Heartwater, induces severe damage to the vascular endothelium in ruminants. Nevertheless, E. ruminantium-induced pathobiology remains largely unknown. Our work paves the way for understanding this phenomenon by using quantitative proteomic analyses (2D-DIGE-MS/MS, 1DE-nanoLC-MS/MS and biotin-nanoUPLC-MS/MS) of host bovine aorta endothelial cells (BAE) during the in vitro bacterium intracellular replication cycle. We detect 265 bacterial proteins (including virulence factors), at all time-points of the E. ruminantium replication cycle, highlighting a dynamic bacterium–host interaction. We show that E. ruminantium infection modulates the expression of 433 host proteins: 98 being over-expressed, 161 under-expressed, 140 detected only in infected BAE cells and 34 exclusively detected in non-infected cells. Cystoscape integrated data analysis shows that these proteins lead to major changes in host cell immune responses, host cell metabolism and vesicle trafficking, with a clear involvement of inflammation-related proteins in this process. Our findings led to the first model of E. ruminantium infection in host cells in vitro, and we highlight potential biomarkers of E. ruminantium infection in endothelial cells (such as ROCK1, TMEM16K, Albumin and PTPN1), which may be important to further combat Heartwater, namely by developing non-antibiotic-based strategies.

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Regulation of Notch signaling by E3 ubiquitin ligases

Cited by 29 publications

References 159 publications

Cleaved Delta like 1 intracellular domain regulates neural development via Notch signal-dependent and -independent pathways

Cleaved Delta like 1 intracellular domain regulates neural development via Notch signal-dependent and -independent pathways

Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Revisiting Ehrlichia ruminantium Replication Cycle Using Proteomics: The Host and the Bacterium Perspectives

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