Ligand-Independent Mechanisms of Notch Activity

Abstract

Interaction between the Notch receptor and Delta-Serrate-Lag2 (DSL) ligands is generally deemed to be the starting point of the Notch signaling cascade, after which, Notch is cleaved and the intracellular domain acts as a transcriptional coactivator. By contrast, Notch protein can become activated independent of ligand stimulus through recently identified endosomal trafficking routes as well as through aberrant regulation of Notch components during Notch trafficking, ubiquitination, and degradation. In this review, we summarize genes implicated in ligand-independent Notch activity and remark on the mechanisms by which this process could occur.

Keywords: Drosophila; Notch signaling; developmental biology; noncanonical cell signaling.

Figure 1

The flow of Notch through endosomes endogenously and in mutant cells. In wild-type cells (marked as green endosomes), Notch can be internalized into either the GPI positive or negative endosomal routes and will be activated or degraded depending on the presence of E3 ligases and temperature. How these routes integrate into the other illustrated scenarios of ligand-independent activity is unknown. In crystal cells, sima-promoted ligand independent Notch activation occurs in Hrs-positive early endosomes. Ligand-independent Notch activity occurs in many mutant tissues as well (marked by red endosomes). Upon loss of DSL ligands, Notch will become activated, however the specific endosomal compartment where this activation occurs is unknown. In lgd mutants and Dx-overexpressing cells, Notch will remain on the lysosomal limiting membrane where activation occurs. In ESCRT mutants, Notch will gather in large irregular endosomes where it will be activated.

Figure 2

Hypotheses regarding S2 cleavage emulators. Simplified schematic of the Notch protein (top left) in a WT endosome. S2 cleavage could be imitated by autodissociation at the S1 site (top right), accidental unfolding of the NRR domain (bottom left), or degradation of the extracellular domain (bottom right).