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The many facets of Notch ligands

Abstract

The Notch signaling pathway regulates a diverse array of cell types and cellular processes and is tightly regulated by ligand binding. Both canonical and noncanonical Notch ligands have been identified that may account for some of the pleiotropic nature associated with Notch signaling. This review focuses on the molecular mechanisms by which Notch ligands function as signaling agonists and antagonists, and discusses different modes of activating ligands as well as findings that support intrinsic ligand signaling activity independent of Notch. Post-translational modification, proteolytic processing, endocytosis and membrane trafficking, as well as interactions with the actin cytoskeleton may contribute to the recently appreciated multifunctionality of Notch ligands. The regulation of Notch ligand expression by other signaling pathways provides a mechanism to coordinate Notch signaling with multiple cellular and developmental cues. The association of Notch ligands with inherited human disorders and cancer highlights the importance of understanding the molecular nature and activities intrinsic to Notch ligands.

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References

  • Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA et al. (2008). Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132: 247–258.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aho S . (2004). Soluble form of Jagged1: unique product of epithelial keratinocytes and a regulator of keratinocyte differentiation. J Cell Biochem 92: 1271–1281.

    CAS  PubMed  Google Scholar 

  • Akai J, Halley PA, Storey KG . (2005). FGF-dependent Notch signaling maintains the spinal cord stem zone. Genes Dev 19: 2877–2887.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Albig AR, Becenti DJ, Roy TG, Schiemann WP . (2008). Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells. Microvasc Res 76: 7–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA . (2004). Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117: 515–526.

    CAS  PubMed  Google Scholar 

  • Aoto J, Chen L . (2007). Bidirectional ephrin/Eph signaling in synaptic functions. Brain Res 1184: 72–80.

    CAS  PubMed  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ . (1999). Notch signaling: cell fate control and signal integration in development. Science 284: 770–776.

    Article  CAS  PubMed  Google Scholar 

  • Ascano JM, Beverly LJ, Capobianco AJ . (2003). The C-terminal PDZ-ligand of JAGGED1 is essential for cellular transformation. J Biol Chem 278: 8771–8779.

    CAS  PubMed  Google Scholar 

  • Bachmann E, Krogh TN, Hojrup P, Skjodt K, Teisner B . (1996). Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology. J Reprod Fertil 107: 279–285.

    CAS  PubMed  Google Scholar 

  • Baker NE, Mlodzik M, Rubin GM . (1990). Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous. Science 250: 1370–1377.

    CAS  PubMed  Google Scholar 

  • Baladron V, Ruiz-Hidalgo MJ, Nueda ML, Diaz-Guerra MJ, Garcia-Ramirez JJ, Bonvini E et al. (2005). dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Exp Cell Res 303: 343–359.

    CAS  PubMed  Google Scholar 

  • Bardin AJ, Schweisguth F . (2006). Bearded family members inhibit Neuralized-mediated endocytosis and signaling activity of Delta in Drosophila. Dev Cell 10: 245–255.

    CAS  PubMed  Google Scholar 

  • Barrantes IB, Elia AJ, Wunsch K, Hrabe de Angelis MH, Mak TW, Rossant J et al. (1999). Interaction between Notch signalling and Lunatic fringe during somite boundary formation in the mouse. Curr Biol 9: 470–480.

    CAS  PubMed  Google Scholar 

  • Barriere H, Nemes C, Lechardeur D, Khan-Mohammad M, Fruh K, Lukacs GL . (2006). Molecular basis of oligoubiquitin-dependent internalization of membrane proteins in Mammalian cells. Traffic 7: 282–297.

    CAS  PubMed  Google Scholar 

  • Barsi JC, Rajendra R, Wu JI, Artzt K . (2005). Mind bomb1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling. Mech Dev 122: 1106–1117.

    CAS  PubMed  Google Scholar 

  • Bland CE, Kimberly P, Rand MD . (2003). Notch induced proteolysis and nuclear localization of the Delta ligand. J Biol Chem 278: 13607–13610.

    CAS  PubMed  Google Scholar 

  • Bray SJ . (2006). Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7: 678–689.

    CAS  PubMed  Google Scholar 

  • Bray SJ, Takada S, Harrison E, Shen SC, Ferguson-Smith AC . (2008). The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila. BMC Dev Biol 8: 11.

    PubMed  PubMed Central  Google Scholar 

  • Brone B, Eggermont J . (2005). PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes. Am J Physiol Cell Physiol 288: C20–C29.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES et al. (2000). Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 24: 438–441.

    CAS  PubMed  Google Scholar 

  • Campos AH, Wang W, Pollman MJ, Gibbons GH . (2002). Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ Res 91: 999–1006.

    CAS  PubMed  Google Scholar 

  • Carmena A, Buff E, Halfon MS, Gisselbrecht S, Jimenez F, Baylies MK et al. (2002). Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm. Dev Biol 244: 226–242.

    CAS  PubMed  Google Scholar 

  • Chen N, Greenwald I . (2004). The lateral signal for LIN-12/Notch in C. elegans vulval development comprises redundant secreted and transmembrane DSL proteins. Dev Cell 6: 183–192.

    CAS  PubMed  Google Scholar 

  • Chen W, Casey Corliss D . (2004). Three modules of zebrafish Mind bomb work cooperatively to promote Delta ubiquitination and endocytosis. Dev Biol 267: 361–373.

    CAS  PubMed  Google Scholar 

  • Cheng P, Gabrilovich D . (2008). Notch signaling in differentiation and function of dendritic cells. Immunol Res 41: 1–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chitnis A . (2006). Why is delta endocytosis required for effective activation of notch? Dev Dyn 235: 886–894.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chitnis A, Henrique D, Lewis J, Ish-Horowicz D, Kintner C . (1995). Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta (see comments). Nature 375: 761–766.

    CAS  PubMed  Google Scholar 

  • Chou YH, Chien CT . (2002). Scabrous controls ommatidial rotation in the Drosophila compound eye. Dev Cell 3: 839–850.

    CAS  PubMed  Google Scholar 

  • Cui XY, Hu QD, Tekaya M, Shimoda Y, Ang BT, Nie DY et al. (2004). NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes. J Biol Chem 279: 25858–25865.

    CAS  PubMed  Google Scholar 

  • Dahlqvist C, Blokzijl A, Chapman G, Falk A, Dannaeus K, Ibanez CF et al. (2003). Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation. Development 130: 6089–6099.

    CAS  PubMed  Google Scholar 

  • Dallas MH, Varnum-Finney B, Delaney C, Kato K, Bernstein ID . (2005). Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells. J Exp Med 201: 1361–1366.

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Celis JF, Bray S . (1997). Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124: 3241–3251.

    CAS  PubMed  Google Scholar 

  • de Joussineau C, Soule J, Martin M, Anguille C, Montcourrier P, Alexandre D . (2003). Delta-promoted filopodia mediate long-range lateral inhibition in Drosophila. Nature 426: 555–559.

    CAS  PubMed  Google Scholar 

  • de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ et al. (1997). Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 124: 1139–1148.

    CAS  PubMed  Google Scholar 

  • Deblandre GA, Lai EC, Kintner C . (2001). Xenopus neuralized is a ubiquitin ligase that interacts with XDelta1 and regulates Notch signaling. Dev Cell 1: 795–806.

    CAS  PubMed  Google Scholar 

  • Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID . (2005). Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 106: 2693–2699.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Delwig A, Bland C, Beem-Miller M, Kimberly P, Rand MD . (2006). Endocytosis-independent mechanisms of Delta ligand proteolysis. Exp Cell Res 312: 1345–1360.

    CAS  PubMed  Google Scholar 

  • Dequeant ML, Glynn E, Gaudenz K, Wahl M, Chen J, Mushegian A et al. (2006). A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314: 1595–1598.

    CAS  PubMed  Google Scholar 

  • Doherty D, Feger G, Younger-Shepherd S, Jan LY, Jan YN . (1996). Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation. Genes Dev 10: 421–434.

    CAS  PubMed  Google Scholar 

  • Dorsky RI, Chang WS, Rapaport DH, Harris WA . (1997). Regulation of neuronal diversity in the Xenopus retina by Delta signalling. Nature 385: 67–70.

    CAS  PubMed  Google Scholar 

  • Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J et al. (2004). Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol 271: 272–290.

    CAS  PubMed  Google Scholar 

  • Dunwoodie SL, Clements M, Sparrow DB, Sa X, Conlon RA, Beddington RS . (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 

  • Dunwoodie SL, Henrique D, Harrison SM, Beddington RS . (1997). Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124: 3065–3076.

    CAS  PubMed  Google Scholar 

  • Dyczynska E, Sun D, Yi H, Sehara-Fujisawa A, Blobel CP, Zolkiewska A . (2007). Proteolytic processing of delta-like 1 by ADAM proteases. J Biol Chem 282: 436–444.

    CAS  PubMed  Google Scholar 

  • Eiraku M, Hirata Y, Takeshima H, Hirano T, Kengaku M . (2002). Delta/notch-like epidermal growth factor (EGF)-related receptor, a novel EGF-like repeat-containing protein targeted to dendrites of developing and adult central nervous system neurons. J Biol Chem 277: 25400–25407.

    CAS  PubMed  Google Scholar 

  • Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T et al. (2005). DNER acts as a neuron-specific Notch ligand during Bergmann glial development. Nat Neurosci 8: 873–880.

    CAS  PubMed  Google Scholar 

  • Emery G, Hutterer A, Berdnik D, Mayer B, Wirtz-Peitz F, Gaitan MG et al. (2005). Asymmetric Rab 11 endosomes regulate delta recycling and specify cell fate in the Drosophila nervous system. Cell 122: 763–773.

    CAS  PubMed  Google Scholar 

  • Estrach S, Ambler CA, Lo Celso C, Hozumi K, Watt FM . (2006). Jagged 1 is a beta-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 133: 4427–4438.

    CAS  PubMed  Google Scholar 

  • Estrach S, Legg J, Watt FM . (2007). Syntenin mediates Delta1-induced cohesiveness of epidermal stem cells in culture. J Cell Sci 120: 2944–2952.

    CAS  PubMed  Google Scholar 

  • Eun SH, Lea K, Overstreet E, Stevens S, Lee JH, Fischer JA . (2006). Identification of genes that interact with Drosophila liquid facets. Genetics 175: 1163–1174.

    PubMed  Google Scholar 

  • Faux CH, Turnley AM, Epa R, Cappai R, Bartlett PF . (2001). Interactions between fibroblast growth factors and Notch regulate neuronal differentiation. J Neurosci 21: 5587–5596.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T, Muskavitch MA et al. (1990). Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61: 523–534.

    CAS  PubMed  Google Scholar 

  • Fitzgerald K, Greenwald I . (1995). Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo. Development 121: 4275–4282.

    CAS  PubMed  Google Scholar 

  • Fiuza UM, Arias AM . (2007). Cell and molecular biology of Notch. J Endocrinol 194: 459–474.

    CAS  PubMed  Google Scholar 

  • Franklin JL, Berechid BE, Cutting FB, Presente A, Chambers CB, Foltz DR et al. (1999). Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1. Curr Biol 9: 1448–1457.

    CAS  PubMed  Google Scholar 

  • Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K, Cordes R et al. (2007). Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. J Cell Biol 178: 465–476.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gibson MA, Hatzinikolas G, Kumaratilake JS, Sandberg LB, Nicholl JK, Sutherland GR et al. (1996). Further characterization of proteins associated with elastic fiber microfibrils including the molecular cloning of MAGP-2 (MP25). J Biol Chem 271: 1096–1103.

    CAS  PubMed  Google Scholar 

  • Gibson MA, Sandberg LB, Grosso LE, Cleary EG . (1991). Complementary DNA cloning establishes microfibril-associated glycoprotein (MAGP) to be a discrete component of the elastin-associated microfibrils. J Biol Chem 266: 7596–7601.

    CAS  PubMed  Google Scholar 

  • Glittenberg M, Pitsouli C, Garvey C, Delidakis C, Bray S . (2006). Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis. EMBO J 25: 4697–4706.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC . (2007). Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14: 295–300.

    CAS  PubMed  Google Scholar 

  • Gridley T . (1997). Notch signaling in vertebrate development and disease. Mol Cell Neurosci 9: 103–108.

    CAS  PubMed  Google Scholar 

  • Gridley T . (2003). Notch signaling and inherited disease syndromes. Hum Mol Genet 12 (Spec No 1): R9–R13.

    CAS  PubMed  Google Scholar 

  • Gupta R, Hong D, Iborra F, Sarno S, Enver T . (2007). NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells. Science 316: 590–593.

    CAS  PubMed  Google Scholar 

  • Hagedorn EJ, Bayraktar JL, Kandachar VR, Bai T, Englert DM, Chang HC . (2006). Drosophila melanogaster auxilin regulates the internalization of Delta to control activity of the Notch signaling pathway. J Cell Biol 173: 443–452.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Haltiwanger RS, Lowe JB . (2004). Role of glycosylation in development. Annu Rev Biochem 73: 491–537.

    CAS  PubMed  Google Scholar 

  • Harris BZ, Lim WA . (2001). Mechanism and role of PDZ domains in signaling complex assembly. J Cell Sci 114: 3219–3231.

    CAS  PubMed  Google Scholar 

  • Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F et al. (2004). Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131: 5539–5550.

    CAS  PubMed  Google Scholar 

  • Hawryluk MJ, Keyel PA, Mishra SK, Watkins SC, Heuser JE, Traub LM . (2006). Epsin 1 is a polyubiquitin-selective clathrin-associated sorting protein. Traffic 7: 262–281.

    CAS  PubMed  Google Scholar 

  • Heath E, Tahri D, Andermarcher E, Schofield P, Fleming S, Boulter CA . (2008). Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene. BMC Dev Biol 8: 18.

    PubMed  PubMed Central  Google Scholar 

  • Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P et al. (2007). Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445: 776–780.

    PubMed  Google Scholar 

  • Henrique D, Hirsinger E, Adam J, Le Roux I, Pourquie O, Ish-Horowicz D et al. (1997). Maintenance of neuroepithelial progenitor cells by Delta–Notch signalling in the embryonic chick retina. Curr Biol 7: 661–670.

    CAS  PubMed  Google Scholar 

  • Hicks C, Johnston SH, diSibio G, Collazo A, Vogt TF, Weinmaster G . (2000). Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nat Cell Biol 2: 515–520.

    CAS  PubMed  Google Scholar 

  • Hicks C, Ladi E, Lindsell C, Hsieh J, Hayward S, Collazo A et al. (2002). A secreted Delta1–Fc fusion protein functions both as an activator and inhibitor of Notch1 signaling. J Neurosci Res 69: 60–71.

    Google Scholar 

  • Hiratochi M, Nagase H, Kuramochi Y, Koh CS, Ohkawara T, Nakayama K . (2007). The Delta intracellular domain mediates TGF-beta/Activin signaling through binding to Smads and has an important bi-directional function in the Notch–Delta signaling pathway. Nucleic Acids Res 35: 912–922.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hofmann M, Schuster-Gossler K, Watabe-Rudolph M, Aulehla A, Herrmann BG, Gossler A . (2004). WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos. Genes Dev 18: 2712–2717.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Holland SJ, GAle NW, Mbamalu G, Yancopoulos G, Henkemeyer M, Pawson T . (1996). Bidirectional signaling through the EPH family receptor Nuk and its transmembrane ligands. Nature 383: 722–725.

    CAS  PubMed  Google Scholar 

  • Horvath CA, Vanden Broeck D, Boulet GA, Bogers J, De Wolf MJ . (2007). Epsin: Inducing membrane curvature. Int J Biochem Cell Biol 39: 1765–1770.

    CAS  PubMed  Google Scholar 

  • Hsiung F, Ramirez-Weber FA, Iwaki DD, Kornberg TB . (2005). Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 437: 560–563.

    CAS  PubMed  Google Scholar 

  • Hsueh YP, Wang TF, Yang FC, Sheng M . (2000). Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404: 298–302.

    CAS  PubMed  Google Scholar 

  • Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T et al. (2003). F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 115: 163–175.

    CAS  PubMed  Google Scholar 

  • Hukriede NA, Gu Y, Fleming RJ . (1997). A dominant-negative form of Serrate acts as a general antagonist of Notch activation. Development 124: 3427–3437.

    CAS  PubMed  Google Scholar 

  • Hurlbut GD, Kankel MW, Lake RJ, Artavanis-Tsakonas S . (2007). Crossing paths with Notch in the hyper-network. Curr Opin Cell Biol 19: 166–175.

    CAS  PubMed  Google Scholar 

  • Ikeuchi T, Sisodia SS . (2003). The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent ‘gamma-secretase’ cleavage. J Biol Chem 278: 7751–7754.

    CAS  PubMed  Google Scholar 

  • Irvine KD . (2008). A notch sweeter. Cell 132: 177–179.

    CAS  PubMed  Google Scholar 

  • Itoh F, Itoh S, Goumans MJ, Valdimarsdottir G, Iso T, Dotto GP et al. (2004). Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells. EMBO J 23: 541–551.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D et al. (2003). Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell 4: 67–82.

    CAS  PubMed  Google Scholar 

  • Itoh T, Erdmann KS, Roux A, Habermann B, Werner H, De Camilli P . (2005). Dynamin and the actin cytoskeleton cooperatively regulate plasma membrane invagination by BAR and F-BAR proteins. Dev Cell 9: 791–804.

    CAS  PubMed  Google Scholar 

  • Jacobsen TL, Brennan K, Arias AM, Muskavitch MA . (1998). Cis-interactions between Delta and Notch modulate neurogenic signalling in Drosophila. Development 125: 4531–4540.

    CAS  PubMed  Google Scholar 

  • Jafar-Nejad H, Andrews HK, Acar M, Bayat V, Wirtz-Peitz F, Mehta SQ et al. (2005). Sec15, a component of the exocyst, promotes notch signaling during the asymmetric division of Drosophila sensory organ precursors. Dev Cell 9: 351–363.

    CAS  PubMed  Google Scholar 

  • Jelen F, Oleksy A, Smietana K, Otlewski J . (2003). PDZ domains—common players in the cell signaling. Acta Biochim Pol 50: 985–1017.

    CAS  PubMed  Google Scholar 

  • Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S et al. (2000). The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 192: 1365–1372.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klein T, Arias AM . (1998). Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development. Development 125: 2951–2962.

    CAS  PubMed  Google Scholar 

  • Klein T, Brennan K, Arias AM . (1997). An intrinsic dominant negative activity of serrate that is modulated during wing development in Drosophila. Dev Biol 189: 123–134.

    CAS  PubMed  Google Scholar 

  • Klueg KM, Muskavitch MA . (1999). Ligand-receptor interactions and trans-endocytosis of Delta, Serrate and Notch: members of the Notch signalling pathway in Drosophila. J Cell Sci 112: 3289–3297.

    CAS  PubMed  Google Scholar 

  • Klueg KM, Parody TR, Muskavitch MA . (1998). Complex proteolytic processing acts on Delta, a transmembrane ligand for Notch, during Drosophila development. Mol Biol Cell 9: 1709–1723.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kluppel M, Wrana JL . (2005). Turning it up a Notch: cross-talk between TGF beta and Notch signaling. Bioessays 27: 115–118.

    PubMed  Google Scholar 

  • Koch U, Lacombe TA, Holland D, Bowman JL, Cohen BL, Egan SE 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.

    CAS  PubMed  Google Scholar 

  • Koch U, Radtke F . (2007). Notch and cancer: a double-edged sword. Cell Mol Life Sci 64: 2746–2762.

    CAS  PubMed  Google Scholar 

  • Kolev V, Kacer D, Trifonova R, Small D, Duarte M, Soldi R et al. (2005). The intracellular domain of Notch ligand Delta1 induces cell growth arrest. FEBS Lett 579: 5798–5802.

    CAS  PubMed  Google Scholar 

  • Koo BK, Lim HS, Song R, Yoon MJ, Yoon KJ, Moon JS et al. (2005a). Mind bomb 1 is essential for generating functional Notch ligands to activate Notch. Development 132: 3459–3470.

    CAS  PubMed  Google Scholar 

  • Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH et al. (2005b). Mind bomb-2 is an E3 ligase for Notch ligand. J Biol Chem 280: 22335–22342.

    CAS  PubMed  Google Scholar 

  • Koo BK, Yoon MJ, Yoon KJ, Im SK, Kim YY, Kim CH et al. (2007). An obligatory role of mind bomb-1 in notch signaling of Mammalian development. PLoS ONE 2: e1221.

    PubMed  PubMed Central  Google Scholar 

  • Koutelou E, Sato S, Tomomori-Sato C, Florens L, Swanson SK, Washburn MP et al. (2008). Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1. J Biol Chem 283: 3846–3853.

    CAS  PubMed  Google Scholar 

  • Krivtsov AV, Rozov FN, Zinovyeva MV, Hendrikx PJ, Jiang Y, Visser JW et al. (2007). Jedi—a novel transmembrane protein expressed in early hematopoietic cells. J Cell Biochem 101: 767–784.

    CAS  PubMed  Google Scholar 

  • Kusumi K, Mimoto MS, Covello KL, Beddington RS, Krumlauf R, Dunwoodie SL . (2004). Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis 39: 115–121.

    CAS  PubMed  Google Scholar 

  • Kusumi K, Sun ES, Kerrebrock AW, Bronson RT, Chi DC, Bulotsky MS et al. (1998). The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nat Genet 19: 274–278.

    CAS  PubMed  Google Scholar 

  • Laborda J, Sausville EA, Hoffman T, Notario V . (1993). dlk, a putative mammalian homeotic gene differentially expressed in small cell lung carcinoma and neuroendocrine tumor cell line. J Biol Chem 268: 3817–3820.

    CAS  PubMed  Google Scholar 

  • Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C, Yang LT et al. (2005). The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 170: 983–992.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lai EC, Deblandre GA, Kintner C, Rubin GM . (2001). Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. Dev Cell 1: 783–794.

    CAS  PubMed  Google Scholar 

  • Lai EC, Roegiers F, Qin X, Jan YN, Rubin GM . (2005). The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta. Development 132: 2319–2332.

    CAS  PubMed  Google Scholar 

  • Lai EC, Rubin GM . (2001a). neuralized functions cell-autonomously to regulate a subset of notch-dependent processes during adult Drosophila development. Dev Biol 231: 217–233.

    CAS  PubMed  Google Scholar 

  • Lai EC, Rubin GM . (2001b). Neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development. Proc Natl Acad Sci USA 98: 5637–5642.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Langevin J, Morgan MJ, Sibarita JB, Aresta S, Murthy M, Schwarz T et al. (2005). Drosophila exocyst components Sec5, Sec6, and Sec15 regulate DE-Cadherin trafficking from recycling endosomes to the plasma membrane. Dev Cell 9: 355–376.

    Google Scholar 

  • LaVoie MJ, Selkoe DJ . (2003). The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 278: 34427–34437.

    CAS  PubMed  Google Scholar 

  • Le Borgne R . (2006). Regulation of Notch signalling by endocytosis and endosomal sorting. Curr Opin Cell Biol 18: 213–222.

    CAS  PubMed  Google Scholar 

  • Le Borgne R, Remaud S, Hamel S, Schweisguth F . (2005). Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila. PLoS Biol 3: e96.

    PubMed  PubMed Central  Google Scholar 

  • Le Borgne R, Schweisguth F . (2003a). Notch signaling: endocytosis makes delta signal better. Curr Biol 13: R273–R275.

    CAS  PubMed  Google Scholar 

  • Le Borgne R, Schweisguth F . (2003b). Unequal segregation of Neuralized biases Notch activation during asymmetric cell division. Dev Cell 5: 139–148.

    CAS  PubMed  Google Scholar 

  • Leask A, Abraham DJ . (2006). All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119: 4803–4810.

    CAS  PubMed  Google Scholar 

  • Lee JH, Volinic JL, Banz C, Yao KM, Thomas MK . (2005). Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1. J Endocrinol 187: 283–292.

    CAS  PubMed  Google Scholar 

  • Lehmann R, Jimenez F, Dietrich U, Campos-Ortega JA . (1983). On the phenotype and development of mutants of early neurogenesis in Drosophila melanogaster. Dev Biol 192: 62–74.

    Google Scholar 

  • Lei L, Xu A, Panin VM, Irvine KD . (2003). An O-fucose site in the ligand binding domain inhibits Notch activation. Development 130: 6411–6421.

    CAS  PubMed  Google Scholar 

  • Leong KG, Karsan A . (2006). Recent insights into the role of Notch signaling in tumorigenesis. Blood 107: 2223–2233.

    CAS  PubMed  Google Scholar 

  • Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M et al. (2007). Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 67: 11244–11253.

    CAS  PubMed  Google Scholar 

  • Lieber T, Kidd S, Young MW . (2002). kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev 16: 209–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Limbourg A, Ploom M, Elligsen D, Sorensen I, Ziegelhoeffer T, Gossler A et al. (2007). Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res 100: 363–371.

    CAS  PubMed  Google Scholar 

  • Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F et al. (2008). Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 26: 279–289.

    CAS  PubMed  Google Scholar 

  • Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP et al. (2003). Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23: 14–25.

    PubMed  PubMed Central  Google Scholar 

  • Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD et al. (2007). Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104: 3219–3224.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Loomes KM, Stevens SA, O'Brien ML, Gonzalez DM, Ryan MJ, Segalov M et al. (2007). Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects. Dev Dyn 236: 2943–2951.

    CAS  PubMed  Google Scholar 

  • Lowell S, Jones P, Le Roux I, Dunne J, Watt FM . (2000). Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol 10: 491–500.

    CAS  PubMed  Google Scholar 

  • Lowell S, Watt FM . (2001). Delta regulates keratinocyte spreading and motility independently of differentiation. Mech Dev 107: 133–140.

    CAS  PubMed  Google Scholar 

  • Lu L, Chen X, Zhang CW, Yang WL, Wu YJ, Sun L et al. (2008). Morphological and functional characterization of predifferentiation of myelinating glia-like cells from human bone marrow stromal cells through activation of F3/Notch signaling in mouse retina. Stem Cells 26: 580–590.

    CAS  PubMed  Google Scholar 

  • McGlinn E, van Bueren KL, Fiorenza S, Mo R, Poh AM, Forrest A et al. (2005). Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development. Mech Dev 122: 1218–1233.

    CAS  PubMed  Google Scholar 

  • Micchelli CA, Rulifson EJ, Blair SS . (1997). The function and regulation of cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate. Development 124: 1485–1495.

    CAS  PubMed  Google Scholar 

  • Minamizato T, Sakamoto K, Liu T, Kokubo H, Katsube K, Perbal B et al. (2007). CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways. Biochem Biophys Res Commun 354: 567–573.

    CAS  PubMed  Google Scholar 

  • Mishra-Gorur K, Rand MD, Perez-Villamil B, Artavanis-Tsakonas S . (2002). Down-regulation of Delta by proteolytic processing. J Cell Biol 159: 313–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miyamoto A, Lau R, Hein PW, Shipley JM, Weinmaster G . (2006). Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation. J Biol Chem 281: 10089–10097.

    CAS  PubMed  Google Scholar 

  • Mizuhara E, Nakatani T, Minaki Y, Sakamoto Y, Ono Y, Takai Y . (2005). MAGI1 recruits Dll1 to cadherin-based adherens junctions and stabilizes it on the cell surface. J Biol Chem 280: 26499–26507.

    CAS  PubMed  Google Scholar 

  • Mlodzik M, Baker NE, Rubin GM . (1990). Isolation and expression of scabrous, a gene regulating neurogenesis in Drosophila. Genes Dev 4: 1848–1861.

    CAS  PubMed  Google Scholar 

  • Mok LP, Qin T, Bardot B, LeComte M, Homayouni A, Ahimou F et al. (2005). Delta activity independent of its activity as a ligand of Notch. BMC Dev Biol 5: 6.

    PubMed  PubMed Central  Google Scholar 

  • Morel V, Le Borgne R, Schweisguth F . (2003). Snail is required for Delta endocytosis and Notch-dependent activation of single-minded expression. Dev Genes Evol 213: 65–72.

    CAS  PubMed  Google Scholar 

  • Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G et al. (2000). Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101: 499–510.

    CAS  PubMed  Google Scholar 

  • Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S . (2005). Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7: 1191–1201.

    PubMed  Google Scholar 

  • Muraguchi T, Takegami Y, Ohtsuka T, Kitajima S, Chandana EP, Omura A et al. (2007). RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci 10: 838–845.

    CAS  PubMed  Google Scholar 

  • Nakata A, Ito T, Nagata M, Hori S, Sekimizu K . (2004). GRIP1tau, a novel PDZ domain-containing transcriptional activator, cooperates with the testis-specific transcription elongation factor SII-T1. Genes Cells 9: 1125–1135.

    CAS  PubMed  Google Scholar 

  • Nanda N, Bao M, Lin H, Clauser K, Komuves L, Quertermous T et al. (2005). Platelet endothelial aggregation receptor 1 (PEAR1), a novel epidermal growth factor repeat-containing transmembrane receptor, participates in platelet contact-induced activation. J Biol Chem 280: 24680–24689.

    CAS  PubMed  Google Scholar 

  • Nehring LC, Miyamoto A, Hein PW, Weinmaster G, Shipley JM . (2005). The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface. J Biol Chem 280: 20349–20355.

    CAS  PubMed  Google Scholar 

  • Nichols JT, Miyamoto A, Olsen SL, D'Souza B, Yao C, Weinmaster G . (2007a). DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 176: 445–458.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nichols JT, Miyamoto A, Weinmaster G . (2007b). Notch signaling—constantly on the move. Traffic 8: 959–969.

    CAS  PubMed  Google Scholar 

  • Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW et al. (2006). Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444: 1032–1037.

    CAS  PubMed  Google Scholar 

  • Nueda ML, Baladron V, Sanchez-Solana B, Ballesteros MA, Laborda J . (2007). The EGF-like protein dlk1 inhibits notch signaling and potentiates adipogenesis of mesenchymal cells. J Mol Biol 367: 1281–1293.

    CAS  PubMed  Google Scholar 

  • Okajima T, Matsuura A, Matsuda T . (2008a). Biological functions of glycosyltransferase genes involved in O-fucose glycan synthesis. J Biochem; e-pub ahead of print, 13 February 2008.

  • Okajima T, Reddy B, Matsuda T, Irvine KD . (2008b). Contributions of chaperone and glycosyltransferase activities of O-fucosyltransferase 1 to Notch signaling. BMC Biol 6: 1.

    PubMed  PubMed Central  Google Scholar 

  • Okajima T, Xu A, Irvine KD . (2003). Modulation of notch-ligand binding by protein O-fucosyltransferase 1 and fringe. J Biol Chem 278: 42340–42345.

    CAS  PubMed  Google Scholar 

  • Osborne BA, Minter LM . (2007). Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol 7: 64–75.

    CAS  PubMed  Google Scholar 

  • Overstreet E, Fitch E, Fischer JA . (2004). Fat facets and Liquid facets promote Delta endocytosis and Delta signaling in the signaling cells. Development 131: 5355–5366.

    CAS  PubMed  Google Scholar 

  • Panin VM, Shao L, Lei L, Moloney DJ, Irvine KD, Haltiwanger RS . (2002). Notch ligands are substrates for EGF protein O-fucosyltransferase and Fringe. J Biol Chem 29: 29.

    Google Scholar 

  • Parks AL, Huppert SS, Muskavitch MA . (1997). The dynamics of neurogenic signalling underlying bristle development in Drosophila melanogaster. Mech Dev 63: 61–74.

    CAS  PubMed  Google Scholar 

  • Parks AL, Klueg KM, Stout JR, Muskavitch MA . (2000). Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127: 1373–1385.

    CAS  PubMed  Google Scholar 

  • Parks AL, Stout JR, Shepard SB, Klueg KM, Dos Santos AA, Parody TR et al. (2006). Structure-function analysis of delta trafficking, receptor binding and signaling in Drosophila. Genetics 174: 1947–1961.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL . (2005). Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65: 8690–8697.

    CAS  PubMed  Google Scholar 

  • Pavlopoulos E, Pitsouli C, Klueg KM, Muskavitch MA, Moschonas NK, Delidakis C . (2001). neuralized Encodes a peripheral membrane protein involved in delta signaling and endocytosis. Dev Cell 1: 807–816.

    CAS  PubMed  Google Scholar 

  • Pfister S, Przemeck GK, Gerber JK, Beckers J, Adamski J, Hrabe de Angelis M . (2003). Interaction of the MAGUK family member Acvrinp1 and the cytoplasmic domain of the Notch ligand Delta1. J Mol Biol 333: 229–235.

    CAS  PubMed  Google Scholar 

  • Piccoli DA, Spinner NB . (2001). Alagille syndrome and the Jagged1 gene. Semin Liver Dis 21: 525–534.

    CAS  PubMed  Google Scholar 

  • Pintar A, De Biasio A, Popovic M, Ivanova N, Pongor S . (2007). The intracellular region of Notch ligands: does the tail make the difference? Biol Direct 2: 19.

    PubMed  PubMed Central  Google Scholar 

  • Pitsouli C, Delidakis C . (2005). The interplay between DSL proteins and ubiquitin ligases in Notch signaling. Development 132: 4041–4050.

    CAS  PubMed  Google Scholar 

  • Powell PA, Wesley C, Spencer S, Cagan RL . (2001). Scabrous complexes with Notch to mediate boundary formation. Nature 409: 626–630.

    CAS  PubMed  Google Scholar 

  • Qi H, Rand MD, Wu X, Sestan N, Wang W, Rakic P et al. (1999). Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science 283: 91–94.

    CAS  PubMed  Google Scholar 

  • Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C . (1999). M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem 274: 23850–23857.

    CAS  PubMed  Google Scholar 

  • Rampal R, Luther KB, Haltiwanger RS . (2007). Notch signaling in normal and disease States: possible therapies related to glycosylation. Curr Mol Med 7: 427–445.

    CAS  PubMed  Google Scholar 

  • Raymond T, Schaller M, Hogaboam CM, Lukacs NW, Rochford R, Kunkel SL . (2007). Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lung inflammation. Proc Am Thorac Soc 4: 635–641.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Renaud O, Simpson P . (2001). Scabrous modifies epithelial cell adhesion and extends the range of lateral signalling during development of the spaced bristle pattern in Drosophila. Dev Biol 240: 361–376.

    CAS  PubMed  Google Scholar 

  • Roca C, Adams RH . (2007). Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21: 2511–2524.

    CAS  PubMed  Google Scholar 

  • Ross DA, Rao PK, Kadesch T . (2004). Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Mol Cell Biol 24: 3505–3513.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roux A, Uyhazi K, Frost A, De Camilli P . (2006). GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature 441: 528–531.

    CAS  PubMed  Google Scholar 

  • Ruan Y, Tecott L, Jiang MM, Jan LY, Jan YN . (2001). Ethanol hypersensitivity and olfactory discrimination defect in mice lacking a homolog of Drosophila neuralized. Proc Natl Acad Sci USA 98: 9907–9912.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sainson RC, Harris AL . (2008). Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies. Angiogenesis 11: 41–51.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M et al. (2002b). The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 277: 29399–29405.

    CAS  PubMed  Google Scholar 

  • Sapir A, Assa-Kunik E, Tsruya R, Schejter E, Shilo BZ . (2005). Unidirectional Notch signaling depends on continuous cleavage of Delta. Development 132: 123–132.

    CAS  PubMed  Google Scholar 

  • Seals DF, Courtneidge SA . (2003). The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 17: 7–30.

    CAS  PubMed  Google Scholar 

  • Seo S, Fujita H, Nakano A, Kang M, Duarte A, Kume T . (2006). The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev Biol 294: 458–470.

    CAS  PubMed  Google Scholar 

  • Seugnet L, Simpson P, Haenlin M . (1997). Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev Biol 192: 585–598.

    CAS  PubMed  Google Scholar 

  • Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T, Kanda Y et al. (1999). Mouse Jagged1 physically interacts with Notch2 and other Notch receptors. Assessment by quantitative methods. J Biol Chem 274: 32961–32969.

    CAS  PubMed  Google Scholar 

  • Shimizu K, Chiba S, Saito T, Kumano K, Takahashi T, Hirai H . (2001). Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation. J Biol Chem 276: 25753–25758.

    CAS  PubMed  Google Scholar 

  • Shimizu K, Chiba S, Saito T, Takahashi T, Kumano K, Hamada Y et al. (2002). Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain. EMBO J 21: 294–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shoji H, Tsuchida K, Kishi H, Yamakawa N, Matsuzaki T, Liu Z et al. (2000). Identification and characterization of a PDZ protein that interacts with activin type II receptors. J Biol Chem 275: 5485–5492.

    CAS  PubMed  Google Scholar 

  • Six E, Ndiaye D, Laabi Y, Brou C, Gupta-Rossi N, Israel A et al. (2003). The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc Natl Acad Sci USA 100: 7638–7643.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Six EM, Ndiaye D, Sauer G, Laabi Y, Athman R, Cumano A et al. (2004). The notch ligand Delta1 recruits Dlg1 at cell–cell contacts and regulates cell migration. J Biol Chem 279: 55818–55826.

    CAS  PubMed  Google Scholar 

  • Skwarek LC, Garroni MK, Commisso C, Boulianne GL . (2007). Neuralized contains a phosphoinositide-binding motif required downstream of ubiquitination for delta endocytosis and notch signaling. Dev Cell 13: 783–795.

    CAS  PubMed  Google Scholar 

  • Small D, Kovalenko D, Kacer D, Liaw L, Landriscina M, Di Serio C et al. (2001). Soluble Jagged 1 represses the function of its transmembrane form to induce the formation of the Src-dependent chord-like phenotype. J Biol Chem 276: 32022–32030.

    CAS  PubMed  Google Scholar 

  • Smas CM, Sul HS . (1993). Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell 73: 725–734.

    CAS  PubMed  Google Scholar 

  • Song R, Koo BK, Yoon KJ, Yoon MJ, Yoo KW, Kim HT et al. (2006). Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1. J Biol Chem 281: 36391–36400.

    CAS  PubMed  Google Scholar 

  • Stahl M, Uemura K, Ge C, Shi S, Tashima Y, Stanley P . (2008). Roles of Pofut1 and O-fucose in mammalian notch signaling. J Biol Chem 283: 13638–13651.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stanley P . (2007). Regulation of Notch signaling by glycosylation. Curr Opin Struct Biol 17: 530–535.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Staub O, Rotin D . (2006). Role of ubiquitylation in cellular membrane transport. Physiol Rev 86: 669–707.

    CAS  PubMed  Google Scholar 

  • Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A et al. (2007). The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104: 3225–3230.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun X, Artavanis-Tsakonas S . (1996). The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands. Development 122: 2465–2474.

    CAS  PubMed  Google Scholar 

  • Sun X, Artavanis-Tsakonas S . (1997). Secreted forms of DELTA and SERRATE define antagonists of Notch signaling in Drosophila. Development 124: 3439–3448.

    CAS  PubMed  Google Scholar 

  • Takahashi Y, Inoue T, Gossler A, Saga Y . (2003). Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites. Development 130: 4259–4268.

    CAS  PubMed  Google Scholar 

  • Takeuchi T, Adachi Y, Ohtsuki Y . (2005). Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma. Am J Pathol 166: 1817–1826.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thibout H, Martinerie C, Creminon C, Godeau F, Boudou P, Le Bouc Y et al. (2003). Characterization of human NOV in biological fluids: an enzyme immunoassay for the quantification of human NOV in sera from patients with diseases of the adrenal gland and of the nervous system. J Clin Endocrinol Metab 88: 327–336.

    CAS  PubMed  Google Scholar 

  • Thurston G, Noguera-Troise I, Yancopoulos GD . (2007). The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7: 327–331.

    CAS  PubMed  Google Scholar 

  • Traub LM, Lukacs GL . (2007). Decoding ubiquitin sorting signals for clathrin-dependent endocytosis by CLASPs. J Cell Sci 120: 543–553.

    CAS  PubMed  Google Scholar 

  • Trifonova R, Small D, Kacer D, Kovalenko D, Kolev V, Mandinova A et al. (2004). The non-transmembrane form of Delta1, but not of Jagged1, induces normal migratory behavior accompanied by fibroblast growth factor receptor 1-dependent transformation. J Biol Chem 279: 13285–13288.

    CAS  PubMed  Google Scholar 

  • Tsuda L, Nagaraj R, Zipursky SL, Banerjee U . (2002). An EGFR/Ebi/Sno pathway promotes delta expression by inactivating Su(H)/SMRTER repression during inductive notch signaling. Cell 110: 625–637.

    CAS  PubMed  Google Scholar 

  • Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O et al. (2007). Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn 236: 1456–1474.

    CAS  PubMed  Google Scholar 

  • Turnpenny PD, Whittock N, Duncan J, Dunwoodie S, Kusumi K, Ellard S . (2003). Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. J Med Genet 40: 333–339.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Varnum-Finney B, Wu L, Yu M, Brashem-Stein C, Staats S, Flowers D et al. (2000). Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. J Cell Sci 113 (Part 23): 4313–4318.

    CAS  PubMed  Google Scholar 

  • Vas V, Szilagyi L, Paloczi K, Uher F . (2004). Soluble Jagged-1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self-renewal in a surrogate in vitro assay. J Leukoc Biol 75: 714–720.

    CAS  PubMed  Google Scholar 

  • Visan I, Tan JB, Yuan JS, Harper JA, Koch U, Guidos CJ . (2006a). Regulation of T lymphopoiesis by Notch1 and Lunatic fringe-mediated competition for intrathymic niches. Nat Immunol 7: 634–643.

    CAS  PubMed  Google Scholar 

  • Visan I, Yuan JS, Tan JB, Cretegny K, Guidos CJ . (2006b). Regulation of intrathymic T-cell development by Lunatic Fringe– Notch1 interactions. Immunol Rev 209: 76–94.

    CAS  PubMed  Google Scholar 

  • Vitt UA, Hsu SY, Hsueh AJ . (2001). Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol 15: 681–694.

    CAS  PubMed  Google Scholar 

  • Vollrath B, Pudney J, Asa S, Leder P, Fitzgerald K . (2001). Isolation of a murine homologue of the Drosophila neuralized gene, a gene required for axonemal integrity in spermatozoa and terminal maturation of the mammary gland. Mol Cell Biol 21: 7481–7494.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Struhl G . (2004). Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development 131: 5367–5380.

    CAS  PubMed  Google Scholar 

  • Wang W, Struhl G . (2005). Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila. Development 132: 2883–2894.

    CAS  PubMed  Google Scholar 

  • Wang Y, Kim KA, Kim JH, Sul HS . (2006). Pref-1, a preadipocyte secreted factor that inhibits adipogenesis. J Nutr 136: 2953–2956.

    CAS  PubMed  Google Scholar 

  • Wang Y, Sul HS . (2006). Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation. Mol Cell Biol 26: 5421–5435.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weinmaster G . (1997). The ins and outs of notch signaling. Mol Cell Neurosci 9: 91–102.

    CAS  PubMed  Google Scholar 

  • Wesley CS . (1999). Notch and wingless regulate expression of cuticle patterning genes. Mol Cell Biol 19: 5743–5758.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Williams CK, Li JL, Murga M, Harris AL, Tosato G . (2006). Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107: 931–939.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wright GJ, Leslie JD, Ariza-McNaughton L, Lewis J . (2004). Delta proteins and MAGI proteins: an interaction of Notch ligands with intracellular scaffolding molecules and its significance for zebrafish development. Development 131: 5659–5669.

    CAS  PubMed  Google Scholar 

  • Wu S, Mehta SQ, Pichaud F, Bellen HJ, Quiocho FA . (2005). Sec15 interacts with Rab11 via a novel domain and affects Rab11 localization in vivo. Nat Struct Mol Biol 12: 879–885.

    CAS  PubMed  Google Scholar 

  • Xu A, Haines N, Dlugosz M, Rana NA, Takeuchi H, Haltiwanger RS et al. (2007). In vitro reconstitution of the modulation of Drosophila Notch-ligand binding by Fringe. J Biol Chem 282: 35153–35162.

    CAS  PubMed  Google Scholar 

  • Yan M, Plowman GD . (2007). Delta-like 4/Notch signaling and its therapeutic implications. Clin Cancer Res 13: 7243–7246.

    CAS  PubMed  Google Scholar 

  • Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G . (2005). Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Biol Cell 16: 927–942.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh E, Dermer M, Commisso C, Zhou L, McGlade CJ, Boulianne GL . (2001). Neuralized functions as an E3 ubiquitin ligase during Drosophila development. Curr Biol 11: 1675–1679.

    CAS  PubMed  Google Scholar 

  • Yeh E, Zhou L, Rudzik N, Boulianne GL . (2000). Neuralized functions cell autonomously to regulate Drosophila sense organ development. EMBO J 19: 4827–4837.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP . (2004). Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23: 1155–1165.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Li Q, Jiang YJ . (2007a). Zebrafish Mib and Mib2 are mutual E3 ubiquitin ligases with common and specific delta substrates. J Mol Biol 366: 1115–1128.

    CAS  PubMed  Google Scholar 

  • Zhang C, Li Q, Lim CH, Qiu X, Jiang YJ . (2007b). The characterization of zebrafish antimorphic mib alleles reveals that Mib and Mind bomb-2 (Mib2) function redundantly. Dev Biol 305: 14–27.

    CAS  PubMed  Google Scholar 

  • Zhang N, Norton CR, 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.

    CAS  PubMed  Google Scholar 

  • Zolkiewska A . (2008). ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci; e-pub ahead of print (doi: 10.1007/s00018-008-7586-4)

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Esra Cagavi for helpful comments and the NIH and AICR for support to GW and BD, respectively.

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D'Souza, B., Miyamoto, A. & Weinmaster, G. The many facets of Notch ligands. Oncogene 27, 5148–5167 (2008). https://doi.org/10.1038/onc.2008.229

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  • DOI: https://doi.org/10.1038/onc.2008.229

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