Mechanisms of Non-canonical Signaling in Health and Disease: Diversity to Take Therapy up a Notch?
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.
KeywordsDrosophila melanogaster Ligand-independent signaling mTOR/Akt signaling Non-canonical activation NF-κB signaling Notch signaling Wnt/β-catenin signaling
Ataxia Telangiectasia Mutated
DNA Damage Response
Endosomal Sorting Complex Required for Transport
Hairy and enhancer of split
Lethal (2) giant discs
Mammalian achaete scute homolog-1
Neural precursor cell expressed developmentally down-regulated protein 4
Notch intracellular domain
Phosphatidylinositol 4,5-Bisphosphate 3-kinase
Suppressor of dx
Suppressor of Hairless
Tuberous Sclerosis 1/2
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.
- Drusenheimer N, Migdal B, Jäckel S et al (2015) The mammalian Orthologs of Drosophila lgd, CC2D1A and CC2D1B, function in the endocytic pathway, but their individual loss of function does not affect Notch signalling. PLoS Genet 11:e1005749. https://doi.org/10.1371/journal.pgen.1005749 CrossRefPubMedPubMedCentralGoogle Scholar
- Maréchal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a012716
- Nair P, Somasundaram K, Krishna S (2003) Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 77(12):7106. https://doi.org/10.1128/jvi.77.12.7106-7112.2003 CrossRefPubMedPubMedCentralGoogle Scholar
- Palmer WH, Jia D, Deng W-M (2014) Cis-interactions between Notch and its ligands block ligand-independent Notch activity. Elife 3. https://doi.org/10.7554/eLife.04415
- Sanalkumar R, Indulekha CL, Divya TS et al (2010) ATF2 maintains a subset of neural progenitors through CBF1/Notch independent Hes-1 expression and synergistically activates the expression of Hes-1 in Notch-dependent neural progenitors. J Neurochem 113:807–818. https://doi.org/10.1111/j.1471-4159.2010.06574.x CrossRefPubMedGoogle Scholar
- Veeraraghavalu K, Subbaiah VK, Srivastava S et al (2005) Complementation of human papillomavirus type 16 E6 and E7 by Jagged1-specific Notch1-phosphatidylinositol 3-kinase signaling involves pleiotropic oncogenic functions independent of CBF1;Su(H);Lag-1 activation. J Virol 79:7889–7898. https://doi.org/10.1128/JVI.79.12.7889-7898.2005 CrossRefPubMedPubMedCentralGoogle Scholar