Reversible and bidirectional signaling of notch ligands

Abstract

The Notch signaling pathway is a direct cell-cell communication system involved in a wide variety of biological processes, and its disruption is observed in several pathologies. The pathway is comprised of a ligand-expressing (sender) cell and a receptor-expressing (receiver) cell. The canonical ligands are members of the Delta/Serrate/Lag-1 (DSL) family of proteins. Their binding to a Notch receptor in a neighboring cell induces a conformational change in the receptor, which will undergo regulated intramembrane proteolysis (RIP), liberating the Notch intracellular domain (NICD). The NICD is translocated to the nucleus and promotes gene transcription. It has been demonstrated that the ligands can also undergo RIP and nuclear translocation, suggesting a function for the ligands in the sender cell and possible bidirectionality of the Notch pathway. Although the complete mechanism of ligand processing is not entirely understood, and its dependence on Notch receptors has not been ruled out. Also, ligands have autonomous functions beyond Notch activation. Here we review the concepts of reverse and bidirectional signalization of DSL proteins and discuss the characteristics that make them more than just ligands of the Notch pathway.

The effects of HPV oncoproteins on host communication networks: Therapeutic connotations

“…In the nucleus, NICD associates with the DNA‐binding protein RBPJκ, Mastermind‐like protein (MAML1), and other co‐activators to form a Notch transcriptional factor complex (Figure 2A). The complex binds to Notch‐responsive elements within the promoters of target genes, which leads to the recruitment of additional coactivators, chromatin remodeling complexes, and the initiation of gene transcription 123 …”

“…The complex binds to Notch-responsive elements within the promoters of target genes, which leads to the recruitment of additional coactivators, chromatin remodeling complexes, and the initiation of gene transcription. 123 Within keratinocytes, Notch signaling plays a crucial role in spinous differentiation-a process known as keratinocyte stratification or epidermal maturation. First, Notch expression helps in maintaining the undifferentiated state of basal keratinocytes, and ensures the compactness of the proliferative compartment of the skin.…”

Comparative Analysis of Alpha and Beta HPV E6 Oncoproteins: Insights into Functional Distinctions and Divergent Mechanisms of Pathogenesis

“…The NICD translocated to the nucleus, associates with the DNA-binding protein RBPJκ, MAML1 (Mastermind-like Transcriptional Coactivator 1), and other co-activators to form a Notch transcriptional factor complex. The complex then binds to Notch-responsive elements and activates the transcription of downstream target genes [156].…”

Sacubitril/valsartan inhibits the proliferation of vascular smooth muscle cells through notch signaling and ERK1/2 pathway

“…The Notch signaling pathway is mainly composed of receptors(Notch1-4), ligands (Jagged-1,2, Delta-like 1, 3, 4), CSL binding proteins, regulators and other effectors [ 5 ]. Notch receptors and ligand genes are first transcribed and translated into proteins, Notch in neighboring cells transactivate receptors release the receptor intracellular domain (NICD) [ 6 ]. Then, it shuttles to the nucleus and binds to recombination signal sequence-binding protein Jκ (RBP- Jκ) in the promoter to regulate downstream gene expression [ 7 ].…”