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Targeting Notch in Cancer pp 87–126Cite as

Out on the Fringe: Modulation of Notch Signaling by Glycosylation

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Abstract

Differential glycosylation of Notch, often as part of a feedback loop, represents a powerful mechanism by which signaling is regulated. Together with Dll (Delta) and Jagged (Serrate) ligands, Fringe, Rumi, and other sugar transferase proteins form a remarkably versatile system to coordinate Notch-dependent tissue patterning. When Fringe is induced in the same cell as Dll, it enhances signal reception through Notch, downregulates Dll through cis-inhibition, and helps to make neighboring cells distinct. When induced in a Jagged-expressing cell, it helps to create a hybrid signal sender/receiver identity with low levels of Notch signal reception, accompanied by (Jagged) signal sending activity without cis-inhibition. In this situation, Fringe can help drive neighbors to the same state. Fringe can even work together with Dll3 to inhibit Notch signaling in neighboring cells. A detailed mechanism by which Fringes control development of several tissues has begun to emerge. With time, studies on Notch glycosylation should help define how this system is used to control development in most tissues and how it can be exploited for therapeutic benefit in the fight against cancer and cardiovascular disease.

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References

  1. Irvine, K. D., & Wieschaus, E. (1994). fringe, a Boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell, 79, 595–606.

    Article  CAS  PubMed  Google Scholar 

  2. Rauskolb, C., Correia, T., & Irvine, K. D. (1999). Fringe-dependent separation of dorsal and ventral cells in the Drosophila wing. Nature, 401, 476–480.

    Article  CAS  PubMed  Google Scholar 

  3. Papayannopoulos, V., Tomlinson, A., Panin, V. M., Rauskolb, C., & Irvine, K. D. (1998). Dorsal-Ventral Signaling in the Drosophila Eye. Science, 281, 2031–2034.

    Article  CAS  PubMed  Google Scholar 

  4. Rauskolb, C., & Irvine, K. D. (1999). Notch-mediated segmentation and growth control of the Drosophila leg. Developmental Biology, 210, 339–350.

    Article  CAS  PubMed  Google Scholar 

  5. Grammont, M., & Irvine, K. D. (2001). fringe and Notch specify polar cell fate during Drosophila oogenesis. Development, 128, 2243–2253.

    CAS  PubMed  Google Scholar 

  6. Grammont, M., & Irvine, K. D. (2002). Organizer activity of the polar cells during Drosophila oogenesis. Development, 129, 5131–5140.

    CAS  PubMed  Google Scholar 

  7. Wu, J. Y., Wen, L., Zhang, W.-J., & Rao, Y. (1996). The secreted product of Xenopus gene lunatic Fringe, a vertebrate signaling molecule. Science, 273, 355–358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Laufer, E., et al. (1997). Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature, 386, 366–373.

    Article  CAS  PubMed  Google Scholar 

  9. Rodriguez-Esteban, C., et al. (1997). Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature, 386, 360–366.

    Article  CAS  PubMed  Google Scholar 

  10. Cohen, B., et al. (1997). Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nature Genetics, 16, 283–288.

    Article  CAS  PubMed  Google Scholar 

  11. Johnston, S. H., et al. (1997). A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development, 124, 2245–2254.

    CAS  PubMed  Google Scholar 

  12. Moran, J. L., et al. (1999). Genomic structure, mapping, and expression analysis of the mammalian Lunatic, Manic, and Radical fringe genes. Mammalian Genome, 10, 535–541.

    Article  CAS  PubMed  Google Scholar 

  13. Moran, J. L., Levorse, J. M., & Vogt, T. F. (1999). Limbs move beyond the radical fringe. Nature, 399, 742–743.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang, N., & Gridley, T. (1999). Reply: Limbs move beyond the Radical Fringe. Nature, 399, 743.

    Article  CAS  Google Scholar 

  15. Zhang, N., Norton, C. R., & Gridley, T. (2002). Segmentation defects of Notch pathway mutants and absence of a synergistic phenotype in lunatic fringe/radical fringe double mutant mice. Genesis, 33, 21–28.

    Article  CAS  PubMed  Google Scholar 

  16. Fleming, R. J., Gu, Y., & Hukriede, N. A. (1997). Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development, 124, 2973–2981.

    CAS  PubMed  Google Scholar 

  17. Panin, V. M., Papayannopoulos, V., Wilson, R., & Irvine, K. D. (1997). Fringe modulates Notch-ligand interactions. Nature, 387, 908–912.

    Article  CAS  PubMed  Google Scholar 

  18. Kim, J., Irvine, K. D., & Carrol, S. B. (1995). Cell recognition, signal induction, and symmetrical gene activation at the Dorsal-Ventral boundary of the developing Drosophila wing. Cell, 82, 795–802.

    Article  CAS  PubMed  Google Scholar 

  19. Troost, T., & Klein, T. (2012). Sequential Notch signalling at the boundary of fringe expressing and non-expressing cells. PLoS One, 7, e49007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yuan, Y. P., Schultz, J., Mlodzik, M., & Bork, P. (1997). Secreted Fringe-like signaling molecules may be glycosyltransferases. Cell, 88, 9–11.

    Article  CAS  PubMed  Google Scholar 

  21. Moloney, D. J., et al. (2000). Mammalian Notch1 Is Modified with Two Unusual Forms of O-Linked Glycosylation Found on Epidermal Growth Factor-like Modules. The Journal of Biological Chemistry, 275, 9604–9611.

    Article  CAS  PubMed  Google Scholar 

  22. Shao, L., Moloney, D. J., & Haltiwanger, R. (2003). Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region. The Journal of Biological Chemistry, 278, 7775–7782.

    Article  CAS  PubMed  Google Scholar 

  23. Panin, V. M., et al. (2002). Notch ligands are substrates for protein O-fucosyltransferase-1 and Fringe. The Journal of Biological Chemistry, 277, 29945–29952.

    Article  CAS  PubMed  Google Scholar 

  24. Rana, N. A., et al. (2011). O-glucose trisaccharide is present at high but variable stoichiometry at multiple sites on mouse Notch1. The Journal of Biological Chemistry, 286, 31623–31637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Moloney, D. J., et al. (2000). Fringe is a glycosyltransferase that modifies Notch. Nature, 406, 369–375.

    Article  CAS  PubMed  Google Scholar 

  26. Bruckner, K., Perez, L., Clausen, H., & Cohen, S. (2000). Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature, 406, 411–415.

    Article  CAS  PubMed  Google Scholar 

  27. Xu, A., et al. (2007). In vitro reconstitution of the modulation of Drosophila Notch-ligand binding by Fringe. The Journal of Biological Chemistry, 282, 35153–35162.

    Article  CAS  PubMed  Google Scholar 

  28. Aoki, K., et al. (2008). The diversity of O-linked glycans expressed during Drosophila melanogaster development reflects stage- and tissue-specific requirements for cell signaling. The Journal of Biological Chemistry, 283, 30385–30400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rana, N. A., & Haltiwanger, R. S. (2011). Fringe benefits: functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors. Current Opinion in Structural Biology, 21, 583–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Correia, T., et al. (2003). Molecular genetic analysis of the glycosyltransferase Fringe in Drosophila. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 100, pp. 6404–6409).

    Google Scholar 

  31. Rampal, R., et al. (2005). Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. The Journal of Biological Chemistry, 280, 42454–42463.

    Article  CAS  PubMed  Google Scholar 

  32. Munro, S., & Freeman, M. (2000). The Notch signalling regulator Fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DxD. Current Biology, 10, 813–820.

    Article  CAS  PubMed  Google Scholar 

  33. Luther, K. B., Schindelin, H., & Haltiwanger, R. S. (2009). Structural and mechanistic insights into lunatic fringe from a kinetic analysis of enzyme mutants. The Journal of Biological Chemistry, 284, 3294–3305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hicks, C., et al. (2000). Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nature Cell Biology, 2, 515–520.

    Article  CAS  PubMed  Google Scholar 

  35. Yang, L. T., et al. (2005). Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Molecular Biology of the Cell, 16, 927–942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, Y., et al. (2001). Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase. The Journal of Biological Chemistry, 276, 40338–40345.

    Article  CAS  PubMed  Google Scholar 

  37. Okajima, T., & Irvine, K. D. (2002). Regulation of notch signaling by o-linked fucose. Cell, 111, 893–904.

    Article  CAS  PubMed  Google Scholar 

  38. Sasamura, T., et al. (2003). neurotic, a novel maternal neurogenic gene, encodes an O-fucosyltransferase that is essential for Notch-Delta interactions. Development, 130, 4785–4795.

    Article  CAS  PubMed  Google Scholar 

  39. Stanley, P., & Guidos, C. J. (2009). Regulation of Notch signaling during T- and B-cell development by O-fucose glycans. Immunology Reviews, 230, 201–215.

    Article  CAS  Google Scholar 

  40. Shi, S., & Stanley, P. (2003). Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 100, pp. 5234–5239).

    Google Scholar 

  41. Yao, D., et al. (2011). Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions. Blood, 117, 5652–5662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ge, C., & Stanley, P. (2008). The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development. In Proceedings of the National Academy of Sciences of the United States of America 105 (pp. 1539–1544).

    Google Scholar 

  43. Rampal, R., Arboleda-Velasquez, J. F., Nita-Lazar, A., Kosik, K. S., & Haltiwanger, R. S. (2005). Highly conserved O-fucose sites have distinct effects on Notch1 function. The Journal of Biological Chemistry, 280, 32133–32140.

    Article  CAS  PubMed  Google Scholar 

  44. Rampal, R., Luther, K. B., & Haltiwanger, R. S. (2007). Notch signaling in normal and disease States: possible therapies related to glycosylation. Current Molecular Medicine, 7, 427–445.

    Article  CAS  PubMed  Google Scholar 

  45. Okajima, T., Xu, A., Lei, L., & Irvine, K. D. (2005). Chaperone activity of protein O-fucosyltransferase 1 promotes notch receptor folding. Science, 307, 1599–1603.

    Article  CAS  PubMed  Google Scholar 

  46. Okajima, T., Reddy, B., Matsuda, T., & Irvine, K. D. (2008). Contributions of chaperone and glycosyltransferase activities of O-fucosyltransferase 1 to Notch signaling. BMC Biology, 6, 1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Okamura, Y., & Saga, Y. (2008). Pofut1 is required for the proper localization of the Notch receptor during mouse development. Mechanisms of Development, 125, 663–673.

    Article  CAS  PubMed  Google Scholar 

  48. Sasamura, T., et al. (2007). The O-fucosyltransferase O-fut1 is an extracellular component that is essential for the constitutive endocytic trafficking of Notch in Drosophila. Development, 134, 1347–1356.

    Article  CAS  PubMed  Google Scholar 

  49. Stahl, M., et al. (2008). Roles of Pofut1 and O-fucose in mammalian Notch signaling. The Journal of Biological Chemistry, 283, 13638–13651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sullivan, F. X., et al. (1998). Molecular cloning of human GDP-mannose 4,6-dehydratase and reconstitution of GDP-fucose biosynthesis in vitro. The Journal of Biological Chemistry, 273, 8193–8202.

    Article  CAS  PubMed  Google Scholar 

  51. Ohyama, C., et al. (1998). Molecular cloning and expression of GDP-D-mannose-4,6-dehydratase, a key enzyme for fucose metabolism defective in Lec13 cells. The Journal of Biological Chemistry, 273, 14582–14587.

    Article  CAS  PubMed  Google Scholar 

  52. Ripka, J., Adamany, A., & Stanley, P. (1986). Two Chinese hamster ovary glycosylation mutants affected in the conversion of GDP-mannose to GDP-fucose. Archives of Biochemistry and Biophysics, 249, 533–545.

    Article  CAS  PubMed  Google Scholar 

  53. Kanda, Y., et al. (2007). Establishment of a GDP-mannose 4,6-dehydratase (GMD) knockout host cell line: a new strategy for generating completely non-fucosylated recombinant therapeutics. Journal of Biotechnology, 130, 300–310.

    Article  CAS  PubMed  Google Scholar 

  54. Jacobsen, T. L., Brennan, K., Arias, A. M., & Muskavitch, M. A. (1998). Cis-interactions between Delta and Notch modulate neurogenic signalling in Drosophila. Development, 125, 4531–4540.

    CAS  PubMed  Google Scholar 

  55. de Celis, J. F., & Bray, S. J. (2000). The Abruptex domain of Notch regulates negative interactions between Notch, its ligands and Fringe. Development, 127, 1291–1302.

    PubMed  Google Scholar 

  56. Sakamoto, K., Ohara, O., Takagi, M., Takeda, S., & Katsube, K. (2002). Intracellular cell-autonomous association of Notch and its ligands: a novel mechanism of Notch signal modification. Developmental Biology, 241, 313–326.

    Article  CAS  PubMed  Google Scholar 

  57. Whiteman, P., et al. (2013). Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor. The Journal of Biological Chemistry, 288, 7305–7312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Luca, V. C., et al. (2015). Structural biology. Structural basis for Notch1 engagement of Delta-like 4. Science, 347, 847–853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Taylor, P., et al. (2014). Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. Proceedings of the National Academy of Sciences of the United States of America, 111, 7290–7295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Andrawes, M. B., et al. (2013). Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1. The Journal of Biological Chemistry, 288, 25477–25489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen, J., Moloney, D. J., & Stanley, P. (2001). Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 98, pp. 13716–13721).

    Google Scholar 

  62. Hou, X., Tashima, Y., & Stanley, P. (2012). Galactose differentially modulates lunatic and manic fringe effects on Delta1-induced NOTCH signaling. The Journal of Biological Chemistry, 287, 474–483.

    Article  CAS  PubMed  Google Scholar 

  63. Tan, J. B., et al. (2009). Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity, 30, 254–263.

    Article  PubMed  CAS  Google Scholar 

  64. Shimizu, K., et al. (2001). Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation. The Journal of Biological Chemistry, 276, 25753–25758.

    Article  CAS  PubMed  Google Scholar 

  65. Van de Walle, I., et al. (2011). Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. Blood, 117, 4449–4459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Muller, J., et al. (2014). O-fucosylation of the notch ligand mDLL1 by POFUT1 is dispensable for ligand function. PLoS One, 9, e88571.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Serth, K., et al. (2015). O-fucosylation of DLL3 is required for its function during somitogenesis. PLoS One, 10, e0123776.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Heuss, S. F., Ndiaye-Lobry, D., Six, E. M., Israel, A., & Logeat, F. (2008). The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. Proceedings of the National Academy of Sciences of the United States of America, 105, 11212–11217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Geffers, I., et al. (2007). Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. Journal of Cell Biology, 178, 465–476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ladi, E., et al. (2005). The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. Journal of Cell Biology, 170, 983–992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang, N., & Gridley, T. (1998). Defects in somite formation in lunatic fringe-deficient mice. Nature, 394, 374–377.

    Article  CAS  PubMed  Google Scholar 

  72. Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L., & Johnson, R. L. (1998). Lunatic fringe is an essential mediator of somite segmentation and patterning. Nature, 394, 377–381.

    Article  CAS  PubMed  Google Scholar 

  73. Conlon, R. A., Reaume, A. G., & Rossant, J. (1995). Notch1 is required for the coordinate segmentation of somites. Development, 121, 1533–1545.

    CAS  PubMed  Google Scholar 

  74. Barrantes, I. B., et al. (1999). Interaction between Notch signalling and Lunatic fringe during somite boundary formation in the mouse. Current Biology, 9, 470–480.

    Article  CAS  PubMed  Google Scholar 

  75. Swiatek, P. J., Lindsell, C. E., Franco del Amo, F., Weinmaster, G., & Gridley, T. (1994). Notch1 is essential for postimplantation development in mice. Genes & Development, 8, 707–719.

    Article  CAS  Google Scholar 

  76. Oka, C., et al. (1995). Disruption of the mouse RBPJk gene results in early embryonic death. Development, 121, 3291–3301.

    CAS  PubMed  Google Scholar 

  77. Hrabe de Angelis, M., McIntyre, J., 2nd, & Gossler, A. (1997). Maintenance of somite borders in mice requires the Delta homologue DII1. Nature, 386, 717–721.

    Article  CAS  PubMed  Google Scholar 

  78. Saga, Y., Hata, N., Koseki, H., & Taketo, M. M. (1997). Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes & Development, 11, 1827–1839.

    Article  CAS  Google Scholar 

  79. Wong, P. C., et al. (1997). Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature, 387, 288–292.

    Article  CAS  PubMed  Google Scholar 

  80. Shen, J., et al. (1997). Skeletal and CNS defects in Presenilin-1-deficient mice. Cell, 89, 629–639.

    Article  CAS  PubMed  Google Scholar 

  81. Kusumi, K., et al. (1998). The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature Genetics, 19, 274–278.

    Article  CAS  PubMed  Google Scholar 

  82. Sparrow, D. B., et al. (2006). Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. American Journal of Human Genetics, 78, 28–37.

    Article  CAS  PubMed  Google Scholar 

  83. Dunwoodie, S. L. (2009). The role of Notch in patterning the human vertebral column. Current Opinion on Genetics & Development, 19, 329–337.

    Article  CAS  Google Scholar 

  84. Chapman, G., Sparrow, D. B., Kremmer, E., & Dunwoodie, S. L. (2011). Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Human Molecular Genetics, 20, 905–916.

    Article  CAS  PubMed  Google Scholar 

  85. McInerney-Leo, A. M., et al. (2015). Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Human Molecular Genetics, 24, 1234–1242.

    Article  CAS  PubMed  Google Scholar 

  86. Sparrow, D. B., Guillen-Navarro, E., Fatkin, D., & Dunwoodie, S. L. (2008). Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Human Molecular Genetics, 17, 3761–3766.

    Article  CAS  PubMed  Google Scholar 

  87. Whittock, N. V., et al. (2004). Mutated MESP2 causes spondylocostal dysostosis in humans. American journal of Human Genetics, 74, 1249–1254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dunwoodie, S. L., et al. (2002). Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development, 129, 1795–1806.

    CAS  PubMed  Google Scholar 

  89. Bulman, M. P., et al. (2000). Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genetics, 24, 438–441.

    Article  CAS  PubMed  Google Scholar 

  90. Sparrow, D. B., Sillence, D., Wouters, M. A., Turnpenny, P. D., & Dunwoodie, S. L. (2010). Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis. European Journal of Human Genetics, 18, 674–679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hubaud, A., & Pourquie, O. (2014). Signalling dynamics in vertebrate segmentation. Nature reviews. Molecular Cell Biology, 15, 709–721.

    CAS  PubMed  Google Scholar 

  92. Pourquie, O. (2011). Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell, 145, 650–663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jiang, Y. J., et al. (2000). Notch signalling and the synchronization of the somite segmentation clock. Nature, 408, 475–479.

    Article  CAS  PubMed  Google Scholar 

  94. Chalamalasetty, R. B., et al. (2011). The Wnt3a/beta-catenin target gene Mesogenin1 controls the segmentation clock by activating a Notch signalling program. Nature Communications, 2, 390.

    Article  PubMed  CAS  Google Scholar 

  95. Vilhais-Neto, G. C., et al. (2010). Rere controls retinoic acid signalling and somite bilateral symmetry. Nature, 463, 953–957.

    Article  CAS  PubMed  Google Scholar 

  96. Aulehla, A., et al. (2003). Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Developmental Cell, 4, 395–406.

    Article  CAS  PubMed  Google Scholar 

  97. Dubrulle, J., McGrew, M. J., & Pourquie, O. (2001). FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell, 106, 219–232.

    Article  CAS  PubMed  Google Scholar 

  98. Sawada, A., et al. (2001). Fgf/MAPK signalling is a crucial positional cue in somite boundary formation. Development, 128, 4873–4880.

    CAS  PubMed  Google Scholar 

  99. Lewis, J. (2003). Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator. Current Biology, 13, 1398–1408.

    Article  CAS  PubMed  Google Scholar 

  100. Hoyle, N. P., & Ish-Horowicz, D. (2013). Transcript processing and export kinetics are rate-limiting steps in expressing vertebrate segmentation clock genes. Proceedings of the National Academy of Sciences of the United States of America, 110, E4316–E4324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Niwa, H. (2007). How is pluripotency determined and maintained? Development, 134, 635–646.

    Article  CAS  PubMed  Google Scholar 

  102. Rossant, J., Zirngibl, R., Cado, D., Shago, M., & Giguere, V. (1991). Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes & Development, 5, 1333–1344.

    Article  CAS  Google Scholar 

  103. Shimozono, S., Iimura, T., Kitaguchi, T., Higashijima, S., & Miyawaki, A. (2013). Visualization of an endogenous retinoic acid gradient across embryonic development. Nature, 496, 363–366.

    Article  CAS  PubMed  Google Scholar 

  104. Diez del Corral, R., et al. (2003). Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron, 40, 65–79.

    Article  CAS  PubMed  Google Scholar 

  105. Dequeant, M. L., et al. (2006). A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science, 314, 1595–1598.

    Article  CAS  PubMed  Google Scholar 

  106. Sewell, W., et al. (2009). Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. Developmental Biology, 329, 400–409.

    Article  CAS  PubMed  Google Scholar 

  107. Dale, J. K., et al. (2003). Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature, 421, 275–278.

    Article  CAS  PubMed  Google Scholar 

  108. Cole, S. E., Levorse, J. M., Tilghman, S. M., & Vogt, T. F. (2002). Clock regulatory elements control cyclic expression of Lunatic fringe during somitogenesis. Developmental Cell, 3, 75–84.

    Article  CAS  PubMed  Google Scholar 

  109. Williams, D. R., Shifley, E. T., Lather, J. D., & Cole, S. E. (2014). Posterior skeletal development and the segmentation clock period are sensitive to Lfng dosage during somitogenesis. Developmental Biology, 388, 159–169.

    Article  CAS  PubMed  Google Scholar 

  110. Shifley, E. T., et al. (2008). Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton. Development, 135, 899–908.

    Article  CAS  PubMed  Google Scholar 

  111. Oginuma, M., et al. (2010). The oscillation of Notch activation, but not its boundary, is required for somite border formation and rostral-caudal patterning within a somite. Development, 137, 1515–1522.

    Article  CAS  PubMed  Google Scholar 

  112. Riley, M. F., Bochter, M. S., Wahi, K., Nuovo, G. J., & Cole, S. E. (2013). Mir-125a-5p-mediated regulation of Lfng is essential for the avian segmentation clock. Developmental Cell, 24, 554–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Nitanda, Y., et al. (2014). 3'-UTR-dependent regulation of mRNA turnover is critical for differential distribution patterns of cyclic gene mRNAs. The FEBS Journal, 281, 146–156.

    Article  CAS  PubMed  Google Scholar 

  114. Shifley, E. T., & Cole, S. E. (2008). Lunatic fringe protein processing by proprotein convertases may contribute to the short protein half-life in the segmentation clock. Biochimica et Biophysica Acta, 1783, 2384–2390.

    Article  CAS  PubMed  Google Scholar 

  115. Okubo, Y., et al. (2012). Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of Notch signalling. Nature Communications, 3, 1141.

    Article  PubMed  CAS  Google Scholar 

  116. Sprinzak, D., et al. (2010). Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature, 465, 86–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. LeBon, L., Lee, T. V., Sprinzak, D., Jafar-Nejad, H., & Elowitz, M. B. (2014). Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states. eLife, 3, e02950.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Matsuda, M., Koga, M., Nishida, E., & Ebisuya, M. (2012). Synthetic signal propagation through direct cell-cell interaction. Science Signaling, 5, ra31.

    Article  PubMed  Google Scholar 

  119. Matsuda, M., Koga, M., Woltjen, K., Nishida, E., & Ebisuya, M. (2015). Synthetic lateral inhibition governs cell-type bifurcation with robust ratios. Nature Communications, 6, 6195.

    Article  CAS  PubMed  Google Scholar 

  120. Kato, T. M., Kawaguchi, A., Kosodo, Y., Niwa, H., & Matsuzaki, F. (2010). Lunatic fringe potentiates Notch signaling in the developing brain. Molecular and Cellular Neurosciences, 45, 12–25.

    Article  CAS  PubMed  Google Scholar 

  121. Manderfield, L. J., et al. (2012). Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation, 125, 314–323.

    Article  PubMed  Google Scholar 

  122. Boareto, M., et al. (2015). Jagged-Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype. Proceedings of the National Academy of Sciences of the United States of America, 112, E402–E409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mullighan, C. G. (2013). Genome sequencing of lymphoid malignancies. Blood, 122, 3899–3907.

    Article  CAS  PubMed  Google Scholar 

  124. Koch, U., & Radtke, F. (2011). Mechanisms of T cell development and transformation. Annual Review of Cell and Developmental Biology, 27, 539–562.

    Article  CAS  PubMed  Google Scholar 

  125. Pajcini, K. V., Speck, N. A., & Pear, W. S. (2011). Notch signaling in mammalian hematopoietic stem cells. Leukemia, 25, 1525–1532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yuan, J. S., Kousis, P. C., Suliman, S., Visan, I., & Guidos, C. J. (2010). Functions of notch signaling in the immune system: consensus and controversies. Annual Review of Immunology, 28, 343–365.

    Article  PubMed  CAS  Google Scholar 

  127. Kumano, K., et al. (2003). Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity, 18, 699–711.

    Article  CAS  PubMed  Google Scholar 

  128. Hadland, B. K., et al. (2004). A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood, 104, 3097–3105.

    Article  CAS  PubMed  Google Scholar 

  129. Guiu, J., et al. (2014). Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence. The Journal of Experimental Medicine, 211, 2411–2423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gama-Norton, L., et al. (2015). Notch signal strength controls cell fate in the haemogenic endothelium. Nature Communications, 6(8510), 8510.

    Article  CAS  PubMed  Google Scholar 

  131. Dzierzak, E., & Speck, N. A. (2008). Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nature Immunology, 9, 129–136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bigas, A., D'Altri, T., & Espinosa, L. (2012). The Notch pathway in hematopoietic stem cells. Current Topics in Microbiology and Immunology, 360, 1–18.

    CAS  PubMed  Google Scholar 

  133. Ayllon, V., et al. (2015). The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fate. Leukemia, 29, 1741–1753.

    Article  CAS  PubMed  Google Scholar 

  134. Jang, I. H., et al. (2015). Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium. Blood, 125, 1418–1426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bigas, A., & Espinosa, L. (2012). Hematopoietic stem cells: to be or Notch to be. Blood, 119, 3226–3235.

    Article  CAS  PubMed  Google Scholar 

  136. Robert-Moreno, A., et al. (2008). Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. The EMBO Journal, 27, 1886–1895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Radtke, F., et al. (1999). Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity, 10, 547–558.

    Article  CAS  PubMed  Google Scholar 

  138. Yu, V. W., et al. (2015). Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. The Journal of Experimental Medicine, 212, 759–774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hozumi, K., et al. (2008). Delta-like 4 is indispensable in thymic environment specific for T cell development. The Journal of Experimental Medicine, 205, 2507–2513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Koch, U., et al. (2008). Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. The Journal of Experimental Medicine, 205, 2515–2523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tan, J. B., Visan, I., Yuan, J. S., & Guidos, C. J. (2005). Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nature Immunology, 6, 671–679.

    Article  CAS  PubMed  Google Scholar 

  142. Yui, M. A., & Rothenberg, E. V. (2014). Developmental gene networks: a triathlon on the course to T cell identity. Nature Reviews. Immunology, 14, 529–545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hoyne, G. F., Chapman, G., Sontani, Y., Pursglove, S. E., & Dunwoodie, S. L. (2011). A cell autonomous role for the Notch ligand Delta-like 3 in alphabeta T-cell development. Immunology and Cell Biology, 89, 696–705.

    Article  CAS  PubMed  Google Scholar 

  144. Visan, I., Yuan, J. S., Tan, J. B., Cretegny, K., & Guidos, C. J. (2006). Regulation of intrathymic T-cell development by Lunatic Fringe- Notch1 interactions. Immunological Reviews, 209, 76–94.

    Article  CAS  PubMed  Google Scholar 

  145. Visan, I., et al. (2006). Regulation of T lymphopoiesis by Notch1 and Lunatic fringe-mediated competition for intrathymic niches. Nature Immunology, 7, 634–643.

    Article  CAS  PubMed  Google Scholar 

  146. Visan, I., Yuan, J. S., Liu, Y., Stanley, P., & Guidos, C. J. (2010). Lunatic fringe enhances competition for delta-like Notch ligands but does not overcome defective pre-TCR signaling during thymocyte beta-selection in vivo. Journal of Immunology, 185, 4609–4617.

    Article  CAS  Google Scholar 

  147. Koch, U., et al. (2001). Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity, 15, 225–236.

    Article  CAS  PubMed  Google Scholar 

  148. Amsen, D., et al. (2007). Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity, 27, 89–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Amsen, D., et al. (2004). Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell, 117, 515–526.

    Article  CAS  PubMed  Google Scholar 

  150. Backer, R. A., et al. (2014). A central role for Notch in effector CD8(+) T cell differentiation. Nature Immunology, 15, 1143–1151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mukherjee, S., et al. (2014). STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease. Journal of Immunology, 192, 996–1003.

    Article  CAS  Google Scholar 

  152. Pillai, S., & Cariappa, A. (2009). The follicular versus marginal zone B lymphocyte cell fate decision. Nature Reviews. Immunology, 9, 767–777.

    Article  CAS  PubMed  Google Scholar 

  153. Fasnacht, N., et al. (2014). Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. The Journal of Experimental Medicine, 211, 2265–2279.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Besseyrias, V., et al. (2007). Hierarchy of Notch-Delta interactions promoting T cell lineage commitment and maturation. The Journal of Experimental Medicine, 204, 331–343.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Hozumi, K., et al. (2004). Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nature Immunology, 5, 638–644.

    Article  CAS  PubMed  Google Scholar 

  156. Saito, T., et al. (2003). Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity, 18, 675–685.

    Article  CAS  PubMed  Google Scholar 

  157. Perou, C. M. (2010). Molecular stratification of triple-negative breast cancers. The Oncologist, 15(Suppl 5), 39–48.

    Article  CAS  PubMed  Google Scholar 

  158. Prat, A., et al. (2010). Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Research, 12, R68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Prat, A., & Perou, C. M. (2009). Mammary development meets cancer genomics. Nature Medicine, 15, 842–844.

    Article  CAS  PubMed  Google Scholar 

  160. Prat, A., et al. (2013). Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. The Oncologist, 18, 123–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Visvader, J. E., & Stingl, J. (2014). Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes & Development, 28, 1143–1158.

    Article  CAS  Google Scholar 

  162. Lim, E., et al. (2009). Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature Medicine, 15, 907–913.

    Article  CAS  PubMed  Google Scholar 

  163. Chaffer, C. L., & Weinberg, R. A. (2011). A perspective on cancer cell metastasis. Science, 331, 1559–1564.

    Article  CAS  PubMed  Google Scholar 

  164. Baccelli, I., & Trumpp, A. (2012). The evolving concept of cancer and metastasis stem cells. The Journal of Cell Biology, 198, 281–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mani, S. A., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Creighton, C. J., Chang, J. C., & Rosen, J. M. (2010). Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. Journal of Mammary Gland Biology and Neoplasia, 15, 253–260.

    Article  PubMed  Google Scholar 

  167. Bouras, T., et al. (2008). Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell, 3, 429–441.

    Article  CAS  PubMed  Google Scholar 

  168. Buono, K. D., et al. (2006). The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy. Developmental Biology, 293, 565–580.

    Article  CAS  PubMed  Google Scholar 

  169. Raouf, A., et al. (2008). Transcriptome analysis of the normal human mammary cell commitment and differentiation process. Cell Stem Cell, 3, 109–118.

    Article  CAS  PubMed  Google Scholar 

  170. Gonzalez, D. M., & Medici, D. (2014). Signaling mechanisms of the epithelial-mesenchymal transition. Science Signaling, 7, re8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Reedijk, M., et al. (2005). High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Research, 65, 8530–8537.

    Article  CAS  PubMed  Google Scholar 

  172. Stoeck, A., et al. (2014). Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma. Cancer Discovery, 4, 1154–1167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wang, K., et al. (2015). PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a gamma-secretase inhibitor. Clinical Cancer Research, 21, 1487–1496.

    Article  CAS  PubMed  Google Scholar 

  174. Robinson, D. R., et al. (2011). Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nature Medicine, 17, 1646–1651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Ling, H., Sylvestre, J. R., & Jolicoeur, P. (2010). Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors. Oncogene, 29, 4543–4554.

    Article  CAS  PubMed  Google Scholar 

  176. Gonzalez, M. E., et al. (2014). EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proceedings of the National Academy of Sciences of the United States of America, 111, 3098–3103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Sale, S., Lafkas, D., & Artavanis-Tsakonas, S. (2013). Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nature Cell Biology, 15, 451–460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lafkas, D., et al. (2013). Notch3 marks clonogenic mammary luminal progenitor cells in vivo. The Journal of Cell Biology, 203, 47–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Ling, H., Sylvestre, J. R., & Jolicoeur, P. (2013). Cyclin D1-dependent induction of luminal inflammatory breast tumors by activated notch3. Cancer Research, 73, 5963–5973.

    Article  CAS  PubMed  Google Scholar 

  180. Pradeep, C. R., et al. (2012). Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling. Oncogene, 31, 907–917.

    Article  CAS  PubMed  Google Scholar 

  181. Harrison, H., et al. (2010). Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Research, 70, 709–718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Simoes, B. M., et al. (2015). Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity. Cell Reports, 12, 1968–1977.

    Article  CAS  PubMed  Google Scholar 

  183. Lombardo, Y., et al. (2014). Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells. Breast Cancer Research, 16, R62.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Brennan, K., & Clarke, R. B. (2013). Combining Notch inhibition with current therapies for breast cancer treatment. Therapeutic Advances in Medical Oncology, 5, 17–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Schott, A. F., et al. (2013). Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clinical Cancer Research, 19, 1512–1524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yen, W. C., et al. (2015). Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clinical Cancer Research, 21, 2084–2095.

    Article  CAS  PubMed  Google Scholar 

  187. Xu, K., et al. (2012). Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell, 21, 626–641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Gastaldi, S., et al. (2013). Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene, 32, 1428–1440.

    Article  CAS  PubMed  Google Scholar 

  189. Graveel, C. R., et al. (2009). Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 106, 12909–12914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Knight, J. F., et al. (2013). Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 110, E1301–E1310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ponzo, M. G., et al. (2009). Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 106, 12903–12908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Zhang, S., Chung, W. C., Miele, L., & Xu, K. (2014). Targeting Met and Notch in the Lfng-deficient, Met-amplified triple-negative breast cancer. Cancer Biology & Therapy, 15, 633–642.

    Article  CAS  Google Scholar 

  193. Zhang, S., et al. (2015). Manic fringe promotes a claudin-low breast cancer phenotype through notch-mediated PIK3CG induction. Cancer Research, 75, 1936–1943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Muellner, M. K., et al. (2011). A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nature Chemical Biology, 7, 787–793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Xie, Y., et al. (2013). Identification of upregulated phosphoinositide 3-kinase gamma as a target to suppress breast cancer cell migration and invasion. Biochemical Pharmacology, 85, 1454–1462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Mazzone, M., et al. (2010). Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proceedings of the National Academy of Sciences of the United States of America, 107, 5012–5017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Xu, K., et al. (2010). Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis. American Journal of Physiology. Lung Cellular and Molecular Physiology, 298, L45–L56.

    Article  CAS  PubMed  Google Scholar 

  198. Lindahl, P., et al. (1999). Role of platelet-derived growth factors in angiogenesis and alveogenesis. Current Topics in Pathology, 93, 27–33.

    Article  CAS  PubMed  Google Scholar 

  199. Tsao, P. N., et al. (2009). Notch signaling controls the balance of ciliated and secretory cell fates in developing airways. Development, 136, 2297–2307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Dang, T. P., Eichenberger, S., Gonzalez, A., Olson, S., & Carbone, D. P. (2003). Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice. Oncogene, 22, 1988–1997.

    Article  CAS  PubMed  Google Scholar 

  201. Guseh, J. S., et al. (2009). Notch signaling promotes airway mucous metaplasia and inhibits alveolar development. Development, 136, 1751–1759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Deimling, J., et al. (2007). Mesenchymal maintenance of distal epithelial cell phenotype during late fetal lung development. American Journal of Physiology. Lung Cellular and Molecular Physiology, 292, L725–L741.

    Article  CAS  PubMed  Google Scholar 

  203. Morimoto, M., Nishinakamura, R., Saga, Y., & Kopan, R. (2012). Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development, 139, 4365–4373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Zhang, S., Loch, A. J., Radtke, F., Egan, S. E., & Xu, K. (2013). Jagged1 is the major regulator of Notch-dependent cell fate in proximal airways. Developmental Dynamics, 242, 678–686.

    Article  CAS  PubMed  Google Scholar 

  205. Kim, C. F., et al. (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell, 121, 823–835.

    Article  CAS  PubMed  Google Scholar 

  206. Neptune, E. R., et al. (2008). Targeted disruption of NeuroD, a proneural basic helix-loop-helix factor, impairs distal lung formation and neuroendocrine morphology in the neonatal lung. The Journal of Biological Chemistry, 283, 21160–21169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Branchfield, K., et al. (2016). Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. Science, 351, 707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Semenova, E. A., Nagel, R., & Berns, A. (2015). Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes & Development, 29, 1447–1462.

    Article  CAS  Google Scholar 

  209. George, J., et al. (2015). Comprehensive genomic profiles of small cell lung cancer. Nature, 524, 47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Moran, J. L., et al. (2009). Manic fringe is not required for embryonic development, and fringe family members do not exhibit redundant functions in the axial skeleton, limb, or hindbrain. Developmental Dynamics, 238, 1803–1812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Berrieman, H. K., et al. (2004). Chromosomal analysis of non-small-cell lung cancer by multicolour fluorescent in situ hybridisation. British Journal of Cancer, 90, 900–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Testa, J. R., et al. (1994). Cytogenetic analysis of 63 non-small cell lung carcinomas: recurrent chromosome alterations amid frequent and widespread genomic upheaval. Genes, Chromosomes & Cancer, 11, 178–194.

    Article  CAS  Google Scholar 

  213. Yi, F., Amarasinghe, B., & Dang, T. P. (2013). Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer. American Journal of Cancer Research, 3, 490–499.

    PubMed  PubMed Central  Google Scholar 

  214. Zhang, Z., et al. (2004). Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models. Oncogene, 23, 3841–3850.

    Article  CAS  PubMed  Google Scholar 

  215. Zheng, Y., et al. (2013). A rare population of CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal. Cancer Cell, 24, 59–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Arasada, R. R., Amann, J. M., Rahman, M. A., Huppert, S. S., & Carbone, D. P. (2014). EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling. Cancer Research, 74, 5572–5584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ryan, D. P., Hong, T. S., & Bardeesy, N. (2014). Pancreatic adenocarcinoma. The New England Journal of Medicine, 371, 2140–2141.

    Article  PubMed  CAS  Google Scholar 

  218. De La, O. J., et al. (2008). Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proceedings of the National Academy of Sciences of the United States of America, 105, 18907–18912.

    Article  Google Scholar 

  219. Maniati, E., et al. (2011). Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. The Journal of Clinical Investigation, 121, 4685–4699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Miyamoto, Y., et al. (2003). Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell, 3, 565–576.

    Article  CAS  PubMed  Google Scholar 

  221. Mazur, P. K., et al. (2010). Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 107, 13438–13443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Hanlon, L., et al. (2010). Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Research, 70, 4280–4286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Avila, J. L., Troutman, S., Durham, A., & Kissil, J. L. (2012). Notch1 is not required for acinar-to-ductal metaplasia in a model of Kras-induced pancreatic ductal adenocarcinoma. PLoS One, 7, e52133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Court, H., et al. (2013). Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression. The Journal of Clinical Investigation, 123, 4681–4694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Ischenko, I., Petrenko, O., & Hayman, M. J. (2014). Analysis of the tumor-initiating and metastatic capacity of PDX1-positive cells from the adult pancreas. Proceedings of the National Academy of Sciences of the United States of America, 111, 3466–3471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Kopp, J. L., et al. (2012). Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell, 22, 737–750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Habbe, N., et al. (2008). Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proceedings of the National Academy of Sciences of the United States of America, 105, 18913–18918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Apelqvist, A., et al. (1999). Notch signalling controls pancreatic cell differentiation. Nature, 400, 877–881.

    Article  CAS  PubMed  Google Scholar 

  229. Kopinke, D., et al. (2012). Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Developmental Biology, 362, 57–64.

    Article  CAS  PubMed  Google Scholar 

  230. Murtaugh, L. C., Stanger, B. Z., Kwan, K. M., & Melton, D. A. (2003). Notch signaling controls multiple steps of pancreatic differentiation. Proceedings of the National Academy of Sciences of the United States of America, 100, 14920–14925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Shih, H. P., et al. (2012). A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development, 139, 2488–2499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Svensson, P., Bergqvist, I., Norlin, S., & Edlund, H. (2009). MFng is dispensable for mouse pancreas development and function. Molecular and Cellular Biology, 29, 2129–2138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Zhang, S., Chung, W. C., & Xu, K. (2015). Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer. Oncogene.

    Google Scholar 

  234. Esni, F., et al. (2004). Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development, 131, 4213–4224.

    Article  CAS  PubMed  Google Scholar 

  235. De Waele, E., Wauters, E., Ling, Z., & Bouwens, L. (2014). Conversion of human pancreatic acinar cells toward a ductal-mesenchymal phenotype and the role of transforming growth factor beta and activin signaling. Pancreas, 43, 1083–1092.

    Article  PubMed  CAS  Google Scholar 

  236. Abel, E. V., et al. (2014). The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS One, 9, e91983.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Bailey, J. M., et al. (2014). DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology, 146, 245–256.

    Article  CAS  PubMed  Google Scholar 

  238. Baumgart, A., et al. (2015). Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model. Oncogene, 34, 578–588.

    Article  CAS  PubMed  Google Scholar 

  239. Doucas, H., et al. (2008). Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. Journal of Surgical Oncology, 97, 63–68.

    Article  PubMed  Google Scholar 

  240. Mann, C. D., et al. (2012). Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma. PLoS One, 7, e51119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Vo, K., et al. (2011). Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation. Molecular Cancer, 10, 138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Lee, S. H., & Shen, M. M. (2015). Cell types of origin for prostate cancer. Current Opinion in Cell Biology, 37, 35–41.

    Article  CAS  PubMed  Google Scholar 

  243. Wu, X., et al. (2011). Differentiation of the ductal epithelium and smooth muscle in the prostate gland are regulated by the Notch/PTEN-dependent mechanism. Developmental Biology, 356, 337–349.

    Article  CAS  PubMed  Google Scholar 

  244. Valdez, J. M., et al. (2012). Notch and TGFbeta form a reciprocal positive regulatory loop that suppresses murine prostate basal stem/progenitor cell activity. Cell Stem Cell, 11, 676–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Kwon, O. J., et al. (2014). Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nature Communications, 5(4416), 4416.

    Article  CAS  PubMed  Google Scholar 

  246. Shou, J., Ross, S., Koeppen, H., de Sauvage, F. J., & Gao, W. Q. (2001). Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Research, 61, 7291–7297.

    CAS  PubMed  Google Scholar 

  247. Santagata, S., et al. (2004). JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Research, 64, 6854–6857.

    Article  CAS  PubMed  Google Scholar 

  248. Zhu, H., Zhou, X., Redfield, S., Lewin, J., & Miele, L. (2013). Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. American Journal of Translational Research, 5, 368–378.

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Domingo-Domenech, J., et al. (2012). Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell, 22, 373–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Danza, G., et al. (2013). Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer. International Journal of Cancer, 133, 2577–2586.

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Pedrosa, A. R., et al. (2015). Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development. Prostate.

    Google Scholar 

  252. Wang, J., et al. (2014). Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages. Nature Communications, 5, 4758.

    Article  CAS  PubMed  Google Scholar 

  253. Ousset, M., et al. (2012). Multipotent and unipotent progenitors contribute to prostate postnatal development. Nature Cell Biology, 14, 1131–1138.

    Article  CAS  PubMed  Google Scholar 

  254. Smith, B. A., et al. (2015). A basal stem cell signature identifies aggressive prostate cancer phenotypes. Proceedings of the National Academy of Sciences of the United States of America, 112, E6544–E6552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Zhang, S., Chung, W. C., Wu, G., Egan, S. E., & Xu, K. (2014). Tumor-suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation. Neoplasia, 16, 158–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Acar, M., et al. (2008). Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell, 132, 247–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Fernandez-Valdivia, R., et al. (2011). Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi. Development, 138, 1925–1934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Takeuchi, H., et al. (2011). Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 108, pp. 16600–16605).

    Google Scholar 

  259. Takeuchi, H., & Haltiwanger, R. S. (2013). Enzymatic analysis of the protein O-glycosyltransferase, Rumi, acting toward epidermal growth factor-like (EGF) repeats. Methods in Molecular Biology, 1022, 119–128.

    Article  CAS  PubMed  Google Scholar 

  260. Haltom, A. R., et al. (2014). The protein O-glucosyltransferase Rumi modifies eyes shut to promote rhabdomere separation in Drosophila. PLoS Genetics, 10, e1004795.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Ramkumar, N., et al. (2015). Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2. PLoS Genetics, 11, e1005551.

    Article  PubMed  PubMed Central  Google Scholar 

  262. Sethi, M. K., et al. (2010). Identification of glycosyltransferase 8 family members as xylosyltransferases acting on O-glucosylated notch epidermal growth factor repeats. The Journal of Biological Chemistry, 285, 1582–1586.

    Article  CAS  PubMed  Google Scholar 

  263. Sethi, M. K., et al. (2012). Molecular cloning of a xylosyltransferase that transfers the second xylose to O-glucosylated epidermal growth factor repeats of notch. The Journal of Biological Chemistry, 287, 2739–2748.

    Article  CAS  PubMed  Google Scholar 

  264. Yu, H., et al. (2015). Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism. Nature Chemical Biology, 11, 847–854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Lee, T. V., et al. (2013). Negative regulation of notch signaling by xylose. PLoS Genetics, 9, e1003547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Huppert, S. S. (2016). A faithful JAGGED1 haploinsufficiency mouse model of arteriohepatic dysplasia (Alagille syndrome) after all. Hepatology, 63, 365–367.

    Article  PubMed  Google Scholar 

  267. Thakurdas, S. M., et al. (2016). Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology, 63, 550–565.

    Article  CAS  PubMed  Google Scholar 

  268. Johansen, K. M., Fehon, R. G., & Artavanis-Tsakonas, S. (1989). The Notch gene product is a glycoprotein expressed on the cell surface of both epidermal and neuronal precursor cells during Drosophila development. The Journal of Cell Biology, 109, 2427–2440.

    Article  CAS  PubMed  Google Scholar 

  269. Dennis, J. W., Lau, K. S., Demetriou, M., & Nabi, I. R. (2009). Adaptive regulation at the cell surface by N-glycosylation. Traffic, 10, 1569–1578.

    Article  CAS  PubMed  Google Scholar 

  270. Stanley, P., & Okajima, T. (2010). Roles of glycosylation in Notch signaling. Current Topics in Developmental Biology, 92, 131–164.

    Article  CAS  PubMed  Google Scholar 

  271. Matsuura, A., et al. (2008). O-linked N-acetylglucosamine is present on the extracellular domain of notch receptors. The Journal of Biological Chemistry, 283, 35486–35495.

    Article  CAS  PubMed  Google Scholar 

  272. Takeuchi, H., & Haltiwanger, R. S. (2014). Significance of glycosylation in Notch signaling. Biochemical and Biophysical Research Communications, 453, 235–242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Tian, J., et al. (2010). Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling. American Journal of Human Genetics, 87, 768–778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Kiecker, C., & Lumsden, A. (2005). Compartments and their boundaries in vertebrate brain development. Nature Reviews. Neuroscience, 6, 553–564.

    Article  CAS  PubMed  Google Scholar 

  275. Tossell, K., Kiecker, C., Wizenmann, A., Lang, E., & Irving, C. (2011). Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser. Development, 138, 3745–3757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Cheng, Y. C., et al. (2004). Notch activation regulates the segregation and differentiation of rhombomere boundary cells in the zebrafish hindbrain. Developmental Cell, 6, 539–550.

    Article  CAS  PubMed  Google Scholar 

  277. Zeltser, L. M., Larsen, C. W., & Lumsden, A. (2001). A new developmental compartment in the forebrain regulated by Lunatic fringe. Nature Neuroscience, 4, 683–684.

    Article  CAS  PubMed  Google Scholar 

  278. Zhang, N., Martin, G. V., Kelley, M. W., & Gridley, T. (2000). A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea. Current Biology, 10, 659–662.

    Article  CAS  PubMed  Google Scholar 

  279. Hartman, B. H., Hayashi, T., Nelson, B. R., Bermingham-McDonogh, O., & Reh, T. A. (2007). Dll3 is expressed in developing hair cells in the mammalian cochlea. Developmental Dynamics, 236, 2875–2883.

    Article  CAS  PubMed  Google Scholar 

  280. Nikolaou, N., et al. (2009). Lunatic fringe promotes the lateral inhibition of neurogenesis. Development, 136, 2523–2533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Stacey, S. M., et al. (2010). Drosophila glial glutamate transporter Eaat1 is regulated by fringe-mediated notch signaling and is essential for larval locomotion. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30, 14446–14457.

    Article  CAS  Google Scholar 

  282. Benedito, R., & Hellstrom, M. (2013). Notch as a hub for signaling in angiogenesis. Experimental Cell Research, 319, 1281–1288.

    Article  CAS  PubMed  Google Scholar 

  283. Benedito, R., et al. (2009). The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell, 137, 1124–1135.

    Article  CAS  PubMed  Google Scholar 

  284. Kofler, N. M., et al. (2011). Notch signaling in developmental and tumor angiogenesis. Genes & Cancer, 2, 1106–1116.

    Article  CAS  Google Scholar 

  285. Holderfield, M. T., et al. (2006). HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes. Biochemical and Biophysical Research Communications, 346, 637–648.

    Article  CAS  PubMed  Google Scholar 

  286. Taylor, K. L., Henderson, A. M., & Hughes, C. C. (2002). Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvascular Research, 64, 372–383.

    Article  CAS  PubMed  Google Scholar 

  287. Pedrosa, A. R., et al. (2015). Endothelial Jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1. Arteriosclerosis, Thrombosis, and Vascular Biology, 35, 1134–1146.

    Article  CAS  PubMed  Google Scholar 

  288. Boareto, M., Jolly, M. K., Ben-Jacob, E., & Onuchic, J. N. (2015). Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision. Proceedings of the National Academy of Sciences of the United States of America, 112, E3836–E3844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. D’Amato, G., et al. (2016). Sequential Notch activation regulates ventricular chamber development. Nature Cell Biology, 18, 7–20.

    Article  PubMed  CAS  Google Scholar 

  290. Pedrosa, A. R., et al. (2015). Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions. Oncotarget, 6, 24404–24423.

    Article  PubMed  PubMed Central  Google Scholar 

  291. Kangsamaksin, T., Tattersall, I. W., & Kitajewski, J. (2014). Notch functions in developmental and tumour angiogenesis by diverse mechanisms. Biochemical Society Transactions, 42, 1563–1568.

    Article  CAS  PubMed  Google Scholar 

  292. Espinoza, I., & Miele, L. (2013). Notch inhibitors for cancer treatment. Pharmacology & Therapeutics, 139, 95–110.

    Article  CAS  Google Scholar 

  293. Wu, Y., et al. (2010). Therapeutic antibody targeting of individual Notch receptors. Nature, 464, 1052–1057.

    Article  CAS  PubMed  Google Scholar 

  294. Ridgway, J., et al. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature, 444, 1083–1087.

    Article  CAS  PubMed  Google Scholar 

  295. Yan, M., et al. (2010). Chronic DLL4 blockade induces vascular neoplasms. Nature, 463, E6–E7.

    Article  CAS  PubMed  Google Scholar 

  296. Andersson, E. R., & Lendahl, U. (2014). Therapeutic modulation of Notch signalling--are we there yet? Nature Reviews. Drug Discovery, 13, 357–378.

    Article  CAS  PubMed  Google Scholar 

  297. May, W. A., et al. (1997). EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic. Nature Genetics, 17, 495–497.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

K.X. is supported by grants from the National Institutes of Health. S.E.E. is supported by grants from the Terry Fox Foundation, the Canadian Breast Cancer Foundation, the Canadian Institutes for Health Research, and the Cancer Research Society. We thank Dr. Cynthia Guidos for valuable comments on the hematopoiesis and lymphocyte development section of the manuscript.

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Authors and Affiliations

  1. Cancer Institute and Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA

    Keli Xu

  2. Program in Cell Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Sean E. Egan

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  1. Keli Xu
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Correspondence to Keli Xu or Sean E. Egan .

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  1. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Lucio Miele

  2. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Spyros Artavanis-Tsakonas

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Xu, K., Egan, S.E. (2018). Out on the Fringe: Modulation of Notch Signaling by Glycosylation. In: Miele, L., Artavanis-Tsakonas, S. (eds) Targeting Notch in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-8859-4_4

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