Journal
CELLS
Volume 9, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/cells9102212
Keywords
NOTCH1; SERCA; T-cell acute lymphoblastic leukemia; thapsigargin; trafficking; CAD204520
Categories
Funding
- AIRC Start-up Investigator Grant [17107]
- Fondazione Cariparma [3576/2017, 0180/2018]
- Leukemia Research Foundation
- Fondazione Grande Ale Onlus
- Feliciani Ferretti Fellowship
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The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane gamma-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known gamma-secretase inhibitors.
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