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

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


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.


Drosophila 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




Late endosome


Lethal (2) giant discs


Mammalian achaete scute homolog-1


Neural precursor cell expressed developmentally down-regulated protein 4


Nuclear Factor-κB


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.


  1. Acosta H, López SL, Revinski DR, Carrasco AE (2011) Notch destabilises maternal beta-catenin and restricts dorsal-anterior development in Xenopus. Development 138:2567–2579. CrossRefPubMedGoogle Scholar
  2. Adamowicz M, Vermezovic J, d’Adda di Fagagna F (2016) NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex. Cell Rep 16:2068–2076. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Andersson ER, Lendahl U (2014) Therapeutic modulation of Notch signalling — are we there yet? Nat Rev Drug Discov 13:357–378. CrossRefPubMedGoogle Scholar
  4. Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138:3593–3612. CrossRefPubMedGoogle Scholar
  5. Artavanis-Tsakonas S, Muskavitch MA, Yedvobnick B (1983) Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster. Proc Natl Acad Sci U S A 80:1977–1981CrossRefPubMedPubMedCentralGoogle Scholar
  6. Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N (1996) Interaction between wingless and Notch signaling pathways mediated by dishevelled. Science 271:1826–1832CrossRefPubMedGoogle Scholar
  7. Banote RK, Edling M, Eliassen F et al (2016) β-Amyloid precursor protein-b is essential for Mauthner cell development in the zebrafish in a Notch-dependent manner. Dev Biol 413:26–38. CrossRefPubMedGoogle Scholar
  8. Becam I, Fiuza UM, Arias AM, Milán M (2010) A role of receptor Notch in ligand cis-inhibition in Drosophila. Curr Biol 20:554–560. CrossRefPubMedGoogle Scholar
  9. Berechid BE, Kitzmann M, Foltz DR et al (2002) Identification and characterization of presenilin-independent Notch signaling. J Biol Chem 277:8154–8165. CrossRefPubMedGoogle Scholar
  10. Berezovska O, Jack C, Deng A et al (2001) Notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage. J Biol Chem 276:30018–30023. CrossRefPubMedGoogle Scholar
  11. Bertrand FE, Angus CW, Partis WJ, Sigounas G (2012) Developmental pathways in colon cancer. Cell Cycle 11:4344–4351. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Blaumueller CM, Qi H, Zagouras P (1997) Intracellular cleavage of notch leads to a heterodimeric receptor on the plasma membrane. Cell 90:281–291CrossRefPubMedGoogle Scholar
  13. Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17:722–735. CrossRefPubMedGoogle Scholar
  14. Brennan K, Baylies M, Arias AM (1999) Repression by Notch is required before Wingless signalling during muscle progenitor cell development in Drosophila. Curr Biol 9:707–710. CrossRefPubMedGoogle Scholar
  15. Bryant PJ, Schubiger G (1971) Giant and duplicated imaginal discs in a new lethal mutant of Drosophila melanogaster. Dev Biol 24:233–263CrossRefPubMedGoogle Scholar
  16. Bush G, Disibio G, Miyamoto A et al (2001) Ligand-induced signaling in the absence of furin processing of Notch1. Dev Biol 229:494–502. CrossRefPubMedGoogle Scholar
  17. Busseau I, Diederich RJ, Xu T, Artavanis-Tsakonas S (1994) A member of the Notch group of interacting loci, deltex encodes a cytoplasmic basic protein. Genetics 136:585–596PubMedPubMedCentralGoogle Scholar
  18. Carvalho FLF, Marchionni L, Gupta A et al (2015) HES6 promotes prostate cancer aggressiveness independently of Notch signalling. J Cell Mol Med 19:1624–1636. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL (2011) Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet 20:905–916. CrossRefPubMedGoogle Scholar
  20. Chastagner P, Israël A, Brou C (2006) Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Rep 7:1147–1153. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chen C-D, Oh S-Y, Hinman JD, Abraham CR (2006) Visualization of APP dimerization and APP-Notch2 heterodimerization in living cells using bimolecular fluorescence complementation. J Neurochem 97:30–43. CrossRefPubMedGoogle Scholar
  22. Childress JL, Acar M, Tao C, Halder G (2006) Lethal Giant discs, a novel C2-domain protein, restricts Notch activation during endocytosis. Curr Biol 16:2228–2233. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Collu GM, Hidalgo-Sastre A, Acar A et al (2012) Dishevelled limits Notch signalling through inhibition of CSL. Development 139:4405–4415. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Cornell M, Evans DA, Mann R et al (1999) The Drosophila melanogaster suppressor of deltex gene, a regulator of the Notch receptor signaling pathway, is an E3 class ubiquitin ligase. Genetics 152:567–576PubMedPubMedCentralGoogle Scholar
  25. Couturier L, Mazouni K, Schweisguth F (2013) Numb localizes at endosomes and controls the endosomal sorting of Notch after asymmetric division in Drosophila. Curr Biol 23:588–593. CrossRefPubMedGoogle Scholar
  26. Dalton HE, Denton D, Foot NJ et al (2011) Drosophila Ndfip is a novel regulator of Notch signaling. Cell Death Differ 18:1150–1160. CrossRefPubMedGoogle Scholar
  27. Deshar R, Cho E-B, Yoon SK, Yoon J-B (2016) CC2D1A and CC2D1B regulate degradation and signaling of EGFR and TLR4. Biochem Biophys Res Commun 480:280–287. CrossRefPubMedGoogle Scholar
  28. Diederich RJ, Matsuno K, Hing H, Artavanis-Tsakonas S (1994) Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. Development 120:473–481PubMedGoogle Scholar
  29. Djiane A, Shimizu H, Wilkin M et al (2011) Su(dx) E3 ubiquitin ligase-dependent and -independent functions of polychaetoid, the Drosophila ZO-1 homologue. J Cell Biol 192:189–200. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Doetzlhofer A, Basch ML, Ohyama T et al (2009) Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell 16:58–69. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Dongre A, Surampudi L, Lawlor RG et al (2014) Non-canonical Notch signaling drives activation and differentiation of peripheral CD4+ T cells. Front Immunol 5:1–14. CrossRefGoogle Scholar
  32. Doran E, Keator D, Head E et al (2017) Down syndrome, partial trisomy 21, and absence of Alzheimer’s disease: the role of APP. J Alzheimers Dis 56:459–470. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Eiraku M, Tohgo A, Ono K et al (2005) DNER acts as a neuron-specific Notch ligand during Bergmann glial development. Nat Neurosci 8:873–880. CrossRefPubMedGoogle Scholar
  35. Endo Y, Osumi N, Wakamatsu Y (2002) Bimodal functions of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development 129:863–873PubMedGoogle Scholar
  36. Endo Y, Osumi N, Wakamatsu Y (2003) Deltex/Dtx mediates NOTCH signaling in regulation of Bmp4 expression in cranial neural crest formation during avian development. Develop Growth Differ 45:241–248. CrossRefGoogle Scholar
  37. Faronato M, Nguyen VTM, Patten DK et al (2015) DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through notch hyper-activation. Oncotarget 6:22467–22479. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Fassa A, Mehta P, Efthimiopoulos S (2005) Notch 1 interacts with the amyloid precursor protein in a Numb-independent manner. J Neurosci Res 82:214–224. CrossRefPubMedGoogle Scholar
  39. Fischer DF, van Dijk R, Sluijs JA et al (2005) Activation of the Notch pathway in down syndrome: cross-talk of Notch and APP. FASEB J 19:1451–1458. CrossRefPubMedGoogle Scholar
  40. Foltz DR, Santiago MC, Berechid BE, Nye JS (2002) Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 12:1006–1011. doi: S0960982202008886 [pii]CrossRefPubMedGoogle Scholar
  41. Fostier M, Evans DA, Artavanis-Tsakonas S, Baron M (1998) Genetic characterization of the Drosophila melanogaster suppressor of deltex gene: a regulator of notch signaling. Genetics 150:1477–1485PubMedPubMedCentralGoogle Scholar
  42. Gallagher CM, Knoblich JA (2006) The conserved C2 domain protein lethal (2) Giant discs regulates protein trafficking in Drosophila. Dev Cell 11:641–653. CrossRefPubMedGoogle Scholar
  43. Gentle ME, Rose A, Bugeon L, Dallman MJ (2012) Noncanonical Notch signaling modulates cytokine responses of dendritic cells to inflammatory stimuli. J Immunol 189:1274–1284. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Greene M, Lai Y, Pajcini K et al (2016) Delta/Notch-like EGF-related receptor (DNER) is not a Notch ligand. PLoS One 11:e0161157. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Guruharsha KG, Kankel MW, Artavanis-Tsakonas S (2012) The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 13:654–666. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Hayashi Y, Nishimune H, Hozumi K et al (2016) A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons. Sci Rep 6:23969. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Hayward P, Brennan K, Sanders P et al (2005) Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity. Development 132:1819–1830. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Herranz H, Stamataki E, Feiguin F et al (2006) Self-refinement of Notch activity through the transmembrane protein crumbs: modulation of gamma-secretase activity. EMBO Rep 7:297–302. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Holleman J, Marchese A (2014) The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein-coupled receptor CXCR4. Mol Biol Cell 25:1892–1904. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Hori K, Fostier M, Ito M et al (2004) Drosophila deltex mediates suppressor of hairless-independent and late-endosomal activation of Notch signaling. Development 131:5527–5537. CrossRefPubMedGoogle Scholar
  51. Hori K, Sen A, Kirchhausen T, Artavanis-Tsakonas S (2011) Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J Cell Biol 195:1005–1015. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Hsieh F-Y, Ma T-L, Shih H-Y et al (2013) Dner inhibits neural progenitor proliferation and induces neuronal and glial differentiation in zebrafish. Dev Biol 375:1–12. CrossRefPubMedGoogle Scholar
  53. Imai Y, Kobayashi Y, Inoshita T et al (2015) The Parkinson’s disease-associated protein kinase LRRK2 modulates Notch signaling through the endosomal pathway. PLoS Genet 11:e1005503. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Ingram WJ, McCue KI, Tran TH et al (2008) Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene 27:1489–1500. CrossRefPubMedGoogle Scholar
  55. Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the notch signaling pathway. J Cell Physiol 194:237–255. CrossRefPubMedGoogle Scholar
  56. Izon DJ, Aster JC, He Y et al (2002) Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 16:231–243. CrossRefPubMedGoogle Scholar
  57. Jaekel R, Klein T (2006) The Drosophila Notch inhibitor and tumor suppressor gene lethal (2) giant discs encodes a conserved regulator of endosomal trafficking. Dev Cell 11:655–669. CrossRefPubMedGoogle Scholar
  58. Jarriault S, Le Bail O, Hirsinger E et al (1998) Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol 18:7423–7431CrossRefPubMedPubMedCentralGoogle Scholar
  59. Jin S, Mutvei AP, Chivukula IV et al (2013) Non-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ. Oncogene 32:4892–4902. CrossRefPubMedGoogle Scholar
  60. Karbowniczek M, Zitserman D, Khabibullin D et al (2010) The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development. J Clin Invest 120:93–102. CrossRefPubMedGoogle Scholar
  61. Kato H, Taniguchi Y, Kurooka H et al (1997) Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development 124:4133–4141. CrossRefPubMedGoogle Scholar
  62. Kiaris H, Politi K, Grimm LM et al (2004) Modulation of Notch signaling elicits signature tumors and inhibits Hras1-induced oncogenesis in the mouse mammary epithelium. Am J Pathol 165:695–705. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Kim IM, Wolf MJ, Rockman HA (2010) Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new Notch ligand. Circ Res 106:1233–1243. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Kim M-Y, Mo J-S, Ann E-J et al (2011) Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk. J Cell Sci 124:1831–1843. CrossRefPubMedGoogle Scholar
  65. Kim S, Sato Y, Mohan PS et al (2016) Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in down syndrome and Alzheimer’s disease. Mol Psychiatry 21:707–716. CrossRefPubMedGoogle Scholar
  66. Kishi N, Tang Z, Maeda Y et al (2001) Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis. Int J Dev Neurosci 19:21–35. CrossRefPubMedGoogle Scholar
  67. Klein T (2003) The tumour suppressor gene l(2)giant discs is required to restrictthe activity of Notch to the dorsoventral boundaryduring Drosophila wing development. Dev Biol 255:313–333. CrossRefPubMedGoogle Scholar
  68. Kobia F, Duchi S, Deflorian G, Vaccari T (2014) Pharmacologic inhibition of vacuolar H+ ATPase reduces physiologic and oncogenic Notch signaling. Mol Oncol 8:207–220. CrossRefPubMedGoogle Scholar
  69. Kopan R, Nye JS, Weintraub H (1994) The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development 120:2385–2396. CrossRefPubMedGoogle Scholar
  70. Kubo F, Nakagawa S (2009) Hairy1 acts as a node downstream of Wnt signaling to maintain retinal stem cell-like progenitor cells in the chick ciliary marginal zone. Development 136:1823–1833. CrossRefPubMedGoogle Scholar
  71. Kuroda K, Tani S, Minoguchi S et al (1999) Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis. J Biol Chem 274:7238–7244CrossRefPubMedGoogle Scholar
  72. Kwon C, Cheng P, King IN et al (2011) Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat Cell Biol 13:1244–1251. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Lieber T, Kidd S, Young MW (2002) Kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev 16:209–221. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Lleó A, Berezovska O, Ramdya P et al (2003) Notch1 competes with the amyloid precursor protein for γ-secretase and down-regulates Presenilin-1 gene expression. J Biol Chem 278:47370–47375. CrossRefPubMedGoogle Scholar
  75. Logeat F, Bessia C, Brou C et al (1998) The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 95:8108–8112CrossRefPubMedPubMedCentralGoogle Scholar
  76. Louvi A, Artavanis-Tsakonas S (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23:473–480. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Ma J, Meng Y, Kwiatkowski DJ et al (2010) Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest 120:103–114. CrossRefPubMedGoogle Scholar
  78. Ma J, Tang X, Wong P et al (2014) Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1-MMP) controls melanoma cell proliferation. J Biol Chem 289:8442–8449. CrossRefPubMedPubMedCentralGoogle Scholar
  79. MacKenzie F, Duriez P, Wong F et al (2004) Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways. J Biol Chem 279:11657–11663. CrossRefPubMedGoogle Scholar
  80. Maliekal TT, Bajaj J, Giri V et al (2008) The role of Notch signaling in human cervical cancer: implications for solid tumors. Oncogene 27:5110–5114. CrossRefPubMedGoogle Scholar
  81. Maréchal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol.
  82. Martinelli N, Hartlieb B, Usami Y et al (2012) CC2D1A is a regulator of ESCRT-III CHMP4B. J Mol Biol 419:75–88. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Matsuno K, Diederich RJ, Go MJ et al (1995) Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development 121:2633–2644PubMedGoogle Scholar
  84. Matsuno K, Eastman D, Mitsiades T et al (1998) Human deltex is a conserved regulator of Notch signalling. Nat Genet 19:74–78. CrossRefPubMedGoogle Scholar
  85. Mazaleyrat SL, Fostier M, Wilkin MB et al (2003) Down-regulation of Notch target gene expression by suppressor of deltex. Dev Biol 255:363–372CrossRefPubMedGoogle Scholar
  86. Merdes G, Soba P, Loewer A et al (2004) Interference of human and Drosophila APP and APP-like proteins with PNS development in Drosophila. EMBO J 23:4082–4095. CrossRefPubMedPubMedCentralGoogle Scholar
  87. Miller AC, Lyons EL, Herman TG (2009) Cis-inhibition of Notch by Endogenous delta biases the outcome of lateral inhibition. Curr Biol 19:1378–1383. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Morawa KS, Schneider M, Klein T (2015) lgd regulates the activity of the BMP/Dpp signalling pathway during Drosophila oogenesis. Development 142:1325–1335. CrossRefPubMedGoogle Scholar
  89. Mukherjee A, Veraksa A, Bauer A et al (2005) Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7:1191–1201. CrossRefPubMedGoogle Scholar
  90. Mukherjee T, Kim WS, Mandal L et al (2011) Interaction between Notch and Hif-alpha in development and survival of Drosophila blood cells. Science 332:1210–1213. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Mungamuri SK1, Yang X, Thor AD, Somasundaram K (2006) Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 66:4715–4724CrossRefPubMedGoogle Scholar
  92. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  93. Nemetschke L, Knust E (2016) Drosophila crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis. Development 143:4543–4553CrossRefPubMedGoogle Scholar
  94. Nofziger D, Miyamoto A, Lyons KM, Weinmaster G (1999) Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts. Development 126:1689–1702PubMedGoogle Scholar
  95. Ordentlich P, Lin A, Shen C et al (1998) Notch inhibition of E47 supports the existence of a novel signaling pathway. Mol Cell Biol 18:2230–2239. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Palmer WH, Jia D, Deng W-M (2014) Cis-interactions between Notch and its ligands block ligand-independent Notch activity. Elife 3.
  97. Pece S, Serresi M, Santolini E et al (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167:215–221. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Pece S, Confalonieri S, Romano P R, Di Fiore PP (2011) NUMB-ing down cancer by more than just a NOTCH. Biochim Biophys Acta–Rev Cancer 1815:26–43. CrossRefGoogle Scholar
  99. Perumalsamy LR, Nagala M, Banerjee P, Sarin A (2009) A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells. Cell Death Differ 16:879–889. CrossRefPubMedGoogle Scholar
  100. Purow B (2012) Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol 727:305–319. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Qiu L, Joazeiro C, Fang N et al (2000) Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem 275:35734–35737CrossRefPubMedGoogle Scholar
  102. Ramain P, Khechumian K, Seugnet L et al (2001) Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate. Curr Biol 11:1729–1738. CrossRefPubMedGoogle Scholar
  103. Rangarajan A, Syal R, Selvarajah S et al (2001) Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology 286:23–30. CrossRefPubMedGoogle Scholar
  104. Richardson ECN, Pichaud F (2010) Crumbs is required to achieve proper organ size control during Drosophila head development. Development 137:641–650. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Roncarati R, Sestan N, Scheinfeld MH et al (2002) The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch signaling. Proc Natl Acad Sci U S A 99:7102–7107. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Sade H, Krishna S, Sarin A (2004) The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 279:2937–2944. CrossRefPubMedGoogle Scholar
  107. Sakata T, Sakaguchi H, Tsuda L et al (2004) Drosophila Nedd4 regulates endocytosis of Notch and suppresses its ligand-independent activation. Curr Biol 14:2228–2236. CrossRefPubMedGoogle Scholar
  108. 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. CrossRefPubMedGoogle Scholar
  109. Sanders PGT, Muñoz-Descalzo S, Balayo T et al (2009) Ligand-independent traffic of notch buffers activated armadillo in Drosophila. PLoS Biol 7:e1000169. CrossRefPubMedPubMedCentralGoogle Scholar
  110. Schneider M, Troost T, Grawe F et al (2013) Activation of Notch in lgd mutant cells requires the fusion of late endosomes with the lysosome. J Cell Sci 126:645–656. CrossRefPubMedGoogle Scholar
  111. Sestan N, Artavanis-Tsakonas S, Rakic P (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746CrossRefPubMedGoogle Scholar
  112. Shawber C, Nofziger D, Hsieh JJ et al (1996) Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway. Development 122:3765–3773PubMedGoogle Scholar
  113. Shimizu H, Woodcock SA, Wilkin MB et al (2014) Compensatory flux changes within an 1’endocytic trafficking network maintain thermal robustness of notch signaling. Cell 157:1160–1174. CrossRefPubMedPubMedCentralGoogle Scholar
  114. Shin HM, Tilahun ME, Cho OH et al (2014) NOTCH1 can initiate NF-kB activation via cytosolic interactions with components of the T cell signalosome. Front Immunol 5:1–15. CrossRefGoogle Scholar
  115. Sprinzak D, Lakhanpal A, LeBon L et al (2011) Mutual inactivation of Notch receptors and ligands facilitates developmental patterning. PLoS Comput Biol 7:e1002069. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Stallwood Y, Briend E, Ray KM et al (2006) Small interfering RNA-mediated knockdown of notch ligands in primary CD4+ T cells and dendritic cells enhances cytokine production. J Immunol 177:885–895CrossRefPubMedGoogle Scholar
  117. Stamos JL, Weis WI (2013) The β-catenin destruction complex. Cold Spring Harb Perspect Biol 5:a007898. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Stockhausen MT, Sjölund J, Axelson H (2005) Regulation of the Notch target gene Hes-1 by TGFα induced Ras/MAPK signaling in human neuroblastoma cells. Exp Cell Res 310:218–228. CrossRefPubMedGoogle Scholar
  119. Tada M, Itoh S, Ishii-Watabe A et al (2012) Functional analysis of the Notch ligand Jagged1 missense mutant proteins underlying Alagille syndrome. FEBS J 279:2096–2107. CrossRefPubMedGoogle Scholar
  120. Tognon E, Kobia F, Busi I et al (2016) Control of lysosomal biogenesis and Notch-dependent tissue patterning by components of the TFEB-V-ATPase axis in Drosophila melanogaster. Autophagy 12:499–514CrossRefPubMedPubMedCentralGoogle Scholar
  121. Troost T, Jaeckel S, Ohlenhard N, Klein T (2012) The tumour suppressor Lethal (2) giant discs is required for the function of the ESCRT-III component Shrub/CHMP4. J Cell Sci 125:763–776. CrossRefPubMedGoogle Scholar
  122. Usami Y, Popov S, Weiss ER et al (2012) Regulation of CHMP4/ESCRT-III function in human immunodeficiency virus type 1 budding by CC2D1A. J Virol 86:3746–3756. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Vaccari T, Lu H, Kanwar R et al (2008) Endosomal entry regulates Notch receptor activation in Drosophila melanogaster. J Cell Biol 180:755–762. CrossRefPubMedPubMedCentralGoogle Scholar
  124. Vaccari T, Duchi S, Cortese K et al (2010) The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development 137:1825–1832. CrossRefPubMedPubMedCentralGoogle Scholar
  125. van Es JH, van Gijn ME, Riccio O et al (2005) Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963. CrossRefPubMedGoogle Scholar
  126. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Vermezovic J, Adamowicz M, Santarpia L et al (2015) Notch is a direct negative regulator of the DNA-damage response. Nat Struct Mol Biol 22:417–424. CrossRefPubMedGoogle Scholar
  128. Wall DS, Mears AJ, McNeill B et al (2009) Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity. J Cell Biol 184:101–112. CrossRefPubMedPubMedCentralGoogle Scholar
  129. Watson KL, Justice RW, Bryant PJ (1994) Drosophila in cancer research: the first fifty tumor suppressor genes. J Cell Sci Suppl 18:19–33CrossRefPubMedGoogle Scholar
  130. Wilkin MB, Carbery A-M, Fostier M et al (2004) Regulation of Notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr Biol 14:2237–2244. CrossRefPubMedGoogle Scholar
  131. Wilkin M, Tongngok P, Gensch N et al (2008) Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of Notch in the endosomal trafficking pathway. Dev Cell 15:762–772. CrossRefPubMedGoogle Scholar
  132. Wu Y, Cain-Hom C, Choy L et al (2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464:1052–1057. CrossRefPubMedGoogle Scholar
  133. Xu T, Artavanis-Tsakonas S (1990) Deltex, a locus interacting with the neurogenic genes, Notch, Delta and mastermind in Drosophila melanogaster. Genetics 126:665–677PubMedPubMedCentralGoogle Scholar
  134. Yamada K, Fuwa TJ, Ayukawa T et al (2011) Roles of Drosophila Deltex in Notch receptor endocytic trafficking and activation. Genes Cells 16:261–272. CrossRefPubMedGoogle Scholar
  135. Yamamoto N, Yamamoto SI, Inagaki F et al (2001) Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor. J Biol Chem 276:45031–45040. CrossRefPubMedGoogle Scholar
  136. Zhao M, Li X-D, Chen Z (2010) CC2D1A, a DM14 and C2 domain protein, activates NF-kappaB through the canonical pathway. J Biol Chem 285:24372–24380. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Zheng L, Saunders CA, Sorensen EB et al (2013) Notch signaling from the endosome requires a conserved dileucine motif. Mol Biol Cell 24:297–307. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© 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

Personalised recommendations