Targeting Notch Trafficking and Processing in Cancers

Abstract

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 γ-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 γ-secretase inhibitors.

Diverse landscape of dermatologic toxicities from small‐molecule inhibitor cancer therapy

“…The Notch family of transmembrane receptors interacts with cellbound ligands upon cell-to-cell contact, at which time the receptors are sequentially cleaved and interact with other signaling pathways (noncanonical function) that translocate to the nucleus to affect target gene expression (canonical function). 277 Aberrant NOTCH signaling is associated with vascular and Alzheimer dementia, and inhibition of the gamma-secretase complex involved in NOTCH cleavage has been identified as a therapeutic target. 278 Dose-dependent dermatologic toxicities in trials of gamma-secretase inhibitors (GSIs) in Alzheimer disease were seen in 40% to 60% of participants and included erythematous (4.5%-5.3%), macular (7%-8%), papular (3%-4%), and maculopapular (3%-8%) rash ($3%-32% cumulatively), pigment changes (13%-19%), and increased incidence of CEP (3%-5% BCC, 5%-6% SCC, 2%-3% AK).…”

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

“…The NOTCH gene was identified in the early 1910s through research on mutant Drosophila melanogaster with serrated wings, which marks the beginning of the story of NOTCH signalling 75 . Haploinsufficiency of NOTCH in fruit flies resulted in wing notches, while complete deficiency proved lethal, inspiring the nomenclature.…”

New focuses on roles of communications between endoplasmic reticulum and mitochondria in identification of biomarkers and targets

“… 71 Dysfunction of those extra‐ER‐origin factors may lead to the disorder of MAMs tensions, ER acidification, γ‐secretase activity, Notch signaling, cell polarity and growth, responsible for the development of cancer or neurodegeneration. 72 , 73 Although the specificity of transporters and regulators during ER‐Mt communication is to be furthermore clarified, it is important to define the enzymatic activity of the target protein, binding to the drug, and drug efficacy in targeting and modulating the structure and function of ER‐Mt contact sites. Many pyrin domain‐containing 3 triggers induce Ca 2+ mobilization from ER and change Mt Ca 2+ uptake in obesity and obesity‐related metabolic diseases with insulin resistance.…”