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

  • Victor Alfred
  • Thomas Vaccari
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)

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.

Keywords

Drosophila melanogaster Ligand-independent signaling mTOR/Akt signaling Non-canonical activation NF-κB signaling Notch signaling Wnt/β-catenin signaling 

Abbreviations

ATM

Ataxia Telangiectasia Mutated

crb

Crumbs

CSL

CBF1/Su(H)/Lag-1

DDR

DNA Damage Response

Dl

Delta

DSL

Delta/Serrate/Lag2

dx

Deltex

ESCRT

Endosomal Sorting Complex Required for Transport

Hes

Hairy and enhancer of split

krz

Kurtz

LE

Late endosome

lgd

Lethal (2) giant discs

Mash1

Mammalian achaete scute homolog-1

Nedd4

Neural precursor cell expressed developmentally down-regulated protein 4

NF-κB

Nuclear Factor-κB

NICD

Notch intracellular domain

PI3K

Phosphatidylinositol 4,5-Bisphosphate 3-kinase

Psn

Presenilin

Su(dx)

Suppressor of dx

Su(H)

Suppressor of Hairless

TSC1/2

Tuberous Sclerosis 1/2

Wg

Wingless

Notes

Acknowledgments

The authors wish to thank E. Morelli for critically reading the manuscript.Work in T.V. laboratory is supported by Worldwide Cancer Research grant #18-0399 and by AIRC (Associazione Italiana Ricerca sul Cancro) Investigator grant #20661.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.IFOM, Istituto FIRC di Oncologia Molecolare at IFOM-IEO CampusMilanItaly
  2. 2.Dipartimento di BioscienzeUniversità degli Studi di MilanoMilanItaly

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