Distinctive properties of the interactions between Notch and Notch ligands

Abstract

Although Notch signaling is known to be critical for the specification of cell fate in various developing organs, the particular roles of each Notch and Notch ligand (NotchL) have not yet been elucidated. The phenotypes found in loss-of-function experiments have varied, depending on the expression profiles of the receptors and ligands. However, in some cases, their significances differ from others, even with comparable levels of expression, suggesting a distinctive functional receptor-ligand interaction during the activation process of Notch signaling. In this review, the phenotypes observed in Notch/NotchL-deficient situations are introduced, and their distinct roles are accentuated. The distinctive features of the specific combinations of Notch/NotchL are also discussed. This review aims to highlight the unanswered questions in this field to help improve our understanding of the preferential functional interaction between Notch and NotchL.

Notch2 complements Notch1 to mediate inductive signaling that initiates early T cell development

“…The implication that Notch1 collaborates with Notch2 in early T lineage cells was unexpected. Among Notch ligands, DLL4 is indispensable to support T cell development in vivo, and it preferentially interacts with Notch1 rather than Notch2 (Hozumi, 2020). To test whether the OP9-DLL1 system could be exaggerating the potency of Notch2, we retested the effects of Notch1 and/or Notch2 deletion using phase 1 cells cocultured on OP9-DLL4 rather than on OP9-DLL1.…”

“…Notch signaling is the main inductive signal for development of T lymphocytes in the thymus (Hozumi, 2020;Radtke et al, 2013). The Notch pathway is evolutionarily conserved and regulates differentiation and organization in diverse organs and cell types.…”

“…Binding of cell surface Notch by Notch ligands triggers proteolytic release of the intracellular domain of Notch (ICN), which translocates to the nucleus to become a coactivator for the DNA binding protein RBPJ. In hematopoiesis, early T cell development in the thymus is the best-studied system for the roles of Notch signaling (Hozumi, 2020;Radtke et al, 2013). Conditional deletion of Notch1 or Delta-like 4 (Dll4) profoundly blocks T cell development and promotes aberrant generation of B cells in the thymus (Hozumi et al, 2008;Radtke et al, 1999).…”

Specific Targeting of Notch Ligand-Receptor Interactions to Modulate Immune Responses: A Review of Clinical and Preclinical Findings

“…While attempts are being made to target Notch in various disease settings, a large number of therapies developed so far have led to undesirable side-effects and toxicities (7). To address these shortcomings, it is important to study the mechanistic and physical aspects of ligand-receptor interactions (68) and role of post-translational modifications such as ligand glycosylation and ubiquitination (32,33,35). It is also necessary to understand how the physiological consequences of ectopic Notch expression are similar to and differ from ligand-specific receptor activation and how different sources of ligands can influence differences in immunological outcomes.…”

Dimerization of the Notch Intracellular Domain Results in Distinct Signaling Activity

“…However, whether it holds this specific function or if it just aids in the stability of the ankyrin domain, which itself has larger implications, is up for debate 63,64 . 65 ).…”