The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force

Abstract

The Notch signaling pathway relies on a proteolytic cascade to release its transcriptionally active intracellular domain, on force to unfold a protective domain and permit proteolysis, on extracellular domain glycosylation to tune the forces exerted by endocytosed ligands, and on a motley crew of nuclear proteins, chromatin modifiers, ubiquitin ligases, and a few kinases to regulate activity and half-life. Herein we provide a review of recent molecular insights into how Notch signals are triggered and how cell shape affects these events, and use the new insights to illuminate a few perplexing observations.

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

“…A number of direct CSL target genes commonly upregulated by its silencing in HKCs and SCC13 cells could be involved in the In Drosophila, it has long been known that the role of Su(H) (CSL homologue) as mediator of NOTCH activation cannot explain the different phenotypes resulting from loss of either gene (14)(15)(16). Increasing evidence indicates that, also in mammalian systems, CSL and NOTCH play only partially overlapping functions.…”

“…While functioning as an essential mediator of Notch activation, CSL is endowed with intrinsic transcription-repressive function and can be converted by other cofactors, besides NOTCH, into an activator (15,16). Evidence from various genetic models indicates that abrogation of CSL function can have consequences beyond suppression of Notch signaling, while conversely, NOTCH activation may involve other mediators besides CSL (15,16). In skin, the more pronounced phenotype of mice with keratinocyte-specific deletion of NOTCH1 and NOTCH2 genes versus CSL suggests that NOTCH has a broader function than CSL (17).…”

Epsin-Dependent Ligand Endocytosis Activates Notch by Force

“…Notch proteins are single-pass transmembrane receptors for cell surface ligands of the Delta/Serrate/Lag2 (DSL) superfamily (reviewed in Kovall et al, 2017). DSL ligands induce extracellular cleavage of the juxtamembrane “Negative Regulatory Region” (NRR) of Notch.…”

“…“Pulling” models posit that Epsin is required after DSL ligands bind Notch, to allow endocytosis of Dl to exert force on the NRR exposing the S2 site for cleavage. Diverse experiments have been taken as evidence for or against these models (Weinmaster and Fischer, 2011; Musse et al, 2012; Kovall et al, 2017). However, this evidence has been more circumstantial than compelling.…”

New Insights into Graft-Versus-Host Disease and Graft Rejection

“…Notch signaling is a highly conserved cell-to-cell communication pathway mediated by Notch ligand-receptor interactions between adjacent cells (Figure 3a) (124). Four Notch receptors (Notch1-4) and five Notch ligands of the Jagged ( Jag) and Delta-like (Dll) families ( Jag1 (117,119,120,122,125,126).…”