Mechanisms of Non-canonical Signaling in Health and Disease: Diversity to Take Therapy up a Notch?

Abstract

Non-canonical Notch signaling encompasses a wide range of cellular processes, diverging considerably from the established paradigm. It can dispense of ligand, proteolytic or nuclear activity. Non-canonical Notch signaling events have been studied mostly in the fruit fly Drosophila melanogaster, the organism in which Notch was identified first and a powerful model for understanding signaling outcomes. However, non-canonical events are ill-defined and their involvement in human physiology is not clear, hampering our understanding of diseases arising from Notch signaling alterations. At a time in which therapies based on specific targeting of Notch signaling are still an unfulfilled promise, detailed understanding of non-canonical Notch events might be key to devising more specific and less toxic pharmacologic options. Based on the blueprint of non-canonical signaling in Drosophila, here, we review and rationalize current evidence about non-canonical Notch signaling. Our effort might inform Notch biologists developing new research avenues and clinicians seeking future treatment of Notch-dependent diseases.

Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

“…For example, Drosophila Notch has been shown to be involved in axon guidance through Abl (Abelson murine leukemia viral oncogene homolog) tyrosine kinase in a manner that does not depend on Su(H) (Giniger, 1998;Kannan et al, 2018). How these and other non-canonical functions of Notch are mechanistically achieved and whether such functions are evolutionarily conserved are still open questions that need to be investigated (Alfred & Vaccari, 2018). How these and other non-canonical functions of Notch are mechanistically achieved and whether such functions are evolutionarily conserved are still open questions that need to be investigated (Alfred & Vaccari, 2018).…”

“…suggesting that N Mcd alleles affect a non-canonical aspect of Notch function (Alfred & Vaccari, 2018;Ramain et al, 2001). Phenotypes seen in N Mcd alleles are dependent on deltex, an endocytic trafficking gene that regulates both ligand-dependent and -independent Notch signaling events (Fuwa et al, 2006;).…”

“…In another example in mammalian cells, NICD was found in the mitochondria where it prevented apoptosis in an RBPJ independent fashion (Perumalsamy, Nagala, & Sarin, 2010). How these and other non-canonical functions of Notch are mechanistically achieved and whether such functions are evolutionarily conserved are still open questions that need to be investigated (Alfred & Vaccari, 2018). By screening for Notch alleles that exhibit unique phenotypes, uncovering the molecular lesions of such mutations, and further understanding the functional impact of these changes on the diverse context of Notch biology, researchers will likely continue to discover unanticipated and exciting aspects of the Notch signaling pathway.…”

Notch signaling in mouse blastocyst development and hatching

“…In mammals, Notch is a receptor-ligand based cell signaling pathway composed of four receptors (Notch1-4) and five ligands (Delta-like (Dll) 1, 3 and 4; Jagged1 and 2). Notch signaling may be conveyed in the so-called canonical and non-canonical forms, reflecting a high mechanistic complexity, yet to be fully understood (for reviews see [20][21][22]).…”

“…Signal termination is ensured by ubiquitin-dependent proteasome degradation of NICD. Knowledge on non-canonical Notch signaling in mammalian systems 4 is still largely fragmentary [22]. This form is ligand independent and/or does not require NICD interaction with Rbpj [23].…”