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.

Keywords: CAD204520; NOTCH1; SERCA; T-cell acute lymphoblastic leukemia; thapsigargin; trafficking.

Figure 1

Schematic representation of Notch signaling and proteolytic processing. NOTCH receptors are cell surface receptor proteins. Interaction with mutual ligands activates two consecutive proteolytic cleavages at the extracellular site, one by a metalloprotease (ADAM10/TACE) (S2), followed by another by a γ-secretase (S3), resulting in the release of N-ICD. N-ICD is translocated into the nucleus where it interacts with a transcription-activating complex. In the presence of NOTCH1 mutations, N-ICD is constitutively active, independent of ligand binding. The figure shows an overview of Notch trafficking routes and the corresponding targets for therapeutic intervention. N-FL: NOTCH full length; N-TM: NOTCH transmembrane; N-ICD: NOTCH intracellular domain.

Figure 2

Overview of NOTCH endocytosis and vesicular trafficking. NOTCH proteins are monoubiquitinated by Deltex, Su(Dx)/Itch, Nedd4, and E3 ligase and endocytosed in clathrin-coated vesicles (CCV), resulting in Rab5-positive early endosomes (EEs). EEs might follow two different routes: (i) recycling back to the membrane through a Rab4/Rab11-positive endosome compartment and (ii) sorting into a Rab7-positive late endosome (LE), followed by ESCRT complex-mediated fusion into multivesicular endosome (MVE). The role of γ-secretase in EE and the release of N-ICD is less clear. From MVE, NOTCH proteins can be ectopically activated or MVE can fuse with the adaptors HOPS and AP-3 and, finally, with lysosomes, enabling NOTCH degradation. CCV: clathrin-coated vesicles; EE: early endosome; LE: late endosome; MVE: multi-vesicular endosome; N-FL: NOTCH full length; N-ICD: NOTCH intracellular domain.