The Multiple Facets of Ubiquitination in the Regulation of Notch Signaling Pathway

Abstract

The Notch signaling pathway regulates numerous aspects of metazoan development and tissue renewal. Deregulation or loss of Notch signaling is associated with a wide range of human disorders from developmental syndromes to cancer. Notch receptors and their ligands are widely expressed throughout development, yet Notch activation is robustly controlled in a spatio-temporal manner. Within the past decades, genetic screens and biochemical approaches led to the identification of more than 10 E3 ubiquitin ligases and deubiquitinating enzymes implicated in the regulation of the Notch pathway. In this review, we highlight the recent studies in Notch signaling that reveal how ubiquitination of components of the Notch pathway, ranging from degradation to regulation of membrane trafficking, impacts on the developmental control of the signaling activities of both Notch receptors and their ligands.

Ubc13 and COOH Terminus of Hsp70-interacting Protein (CHIP) Are Required for Growth Hormone Receptor Endocytosis

“…The role of ubiquitin in endocytosis remains unclear: on the one hand, cargo-specific ubiquitination may be required to enable binding to the UBD of an adaptor; on the other hand, monoubiquitination of the adaptor (Eps15, Epsin) may be inhibitory because of its closed conformation. Because CHIP ubiquitinates Epsin, it is probably a negative factor in the endocytosis of cargo that needs Epsin for endocytosis such as in the case of Notch and the EGF receptor (45)(46)(47). In this study, CHIP is clearly acting as a positive factor for GHR endocytosis.…”

Original Research: Featured Article: Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development

“…A primary effect of Gleevec treatment is the inhibition of GSK3b phosphorylation, unphosphorylated GSK3b is activated, and phosphorylates Int3 marking it for ubiquitination. The Notch-ICD is ubiquitinated by E3 ubiquitin ligases, 28 such as Fbw7 (also known as Cdc4 and Sel10), that can ubiquitinate Notch-ICD within its PEST domain, leading to its proteasomal degradation. [30][31][32]39 It has also been shown that the interaction between Sel-10 and Notch proteins is phosphorylation dependent, 32 suggesting that Notch-ICD phosphorylation precedes its ubiquitination.…”

“…Notch receptors and their ligands are potential substrates for ubiquitin addition by E3 ligases. [27][28][29] It has been demonstrated that Notch-ICD is rapidly polyubiquitinated and degraded through the proteasomal pathway, and the E3 ubiquitin ligase accounting for these modifications is Fbw7/Sel-10. [30][31][32] To elucidate the mechanism by which Gleevec inhibits Notch signaling, we established in vitro and in vivo systems using cell lines and transgenic mice.…”

Endocytosis in Notch Signaling Activation

“…These results, together with the observation that presenilin works optimally in an acidic environment such as that present in the endosome/lysosome [283], support the idea that endosomal sorting of Notch is required for best activation of its S3 cleavage. However, unrestricted access of Notch receptors to the endosome should be prevented, since the acidic pH could dissociate the NECD, thus triggering ligand-independent Notch activation [210].…”

“…Genetic evidence in invertebrates and mammals points to ubiquitylation (also referred to as ubiquitination) as the master regulatory mechanism controlling the endocytosis implicated in Notch signaling activation (reviewed in [209][210][211]). Ubiquitylation, i.e.…”