BioPAX pathway converted from "NOTCH1 binds DLL4" in the Reactome database. LEFT-TO-RIGHT NOTCH1 binds DLL4 NOTCH1 is activated by DLL4 ligand expressed on a neighboring cell. The interaction of NOTCH1 and DLL4 is enhanced when NOTCH1 is glycosylated by fringe-enzymes. Based on mouse studies, activation of NOTCH1 by DLL4 may be important in angiogenesis (Benedito et al. 2009). DLL4 may also be involved in T-cell development. Mouse Dll4 is expressed on thymic epithelial cells and its interaction with Notch1 expressed on hematopoietic progenitors is necessary for T-cell lineage commitment (Koch et al. 2008, Hozumi et al. 2008). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 DLL4 Delta 4 ligand Reactome DB_ID: 158437 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q9NR61 DLL4 DLL4 UNQ1895/PRO4341 FUNCTION Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).SUBUNIT Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).TISSUE SPECIFICITY Expressed in vascular endothelium.DOMAIN The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor. Homo sapiens NCBI Taxonomy 9606 UniProt Q9NR61 27 EQUAL 685 EQUAL Reactome Database ID Release 82 158437 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=158437 Reactome R-HSA-158437 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-158437.1 Reactome http://www.reactome.org Converted from EntitySet in Reactome NOTCH1/Fringe-modified NOTCH1 Reactome DB_ID: 1911555 NOTCH1 NTM-NEC 1 heterodimer Reactome DB_ID: 157027 NOTCH1 Extracellular fragment (NECD1) 19xFucT-16xGlcS-2xFucS-NOTCH1(19-1664) Reactome DB_ID: 1983670 extracellular region GENE ONTOLOGY GO:0005576 UniProt:P46531 NOTCH1 NOTCH1 TAN1 FUNCTION Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1 (PubMed:11101851, PubMed:12370315). The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ (PubMed:10713164). The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (PubMed:17573339). Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts (via NICD) with MDM2A. Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transcractivation activity. Interacts with THBS4 (By similarity). Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (PubMed:12050162). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (By similarity). Interacts with ZMIZ1. Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain). Interacts with DLL1 and JAG1 (By similarity). Interacts (via NICD domain) with PRAG1 (By similarity). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30598546). Interacts with ZFP64 (By similarity).TISSUE SPECIFICITY In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.DOMAIN Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).PTM Phosphorylated.PTM O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).PTM Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).PTM Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).SIMILARITY Belongs to the NOTCH family. UniProt P46531 73 EQUAL O-fucosyl-L-threonine MOD MOD:00813 116 EQUAL 194 EQUAL 232 EQUAL 311 EQUAL 349 EQUAL 466 EQUAL 617 EQUAL 692 EQUAL 767 EQUAL 805 EQUAL 883 EQUAL O-fucosyl-L-serine MOD MOD:00812 921 EQUAL 997 EQUAL 1035 EQUAL 1159 EQUAL 1197 EQUAL 1243 EQUAL 1321 EQUAL 1362 EQUAL 1402 EQUAL 65 EQUAL O-glucosyl-L-serine MOD MOD:00804 146 EQUAL 378 EQUAL 458 EQUAL 496 EQUAL 534 EQUAL 609 EQUAL 647 EQUAL 722 EQUAL 759 EQUAL 797 EQUAL 951 EQUAL 1027 EQUAL 1065 EQUAL 1189 EQUAL 1273 EQUAL 19 EQUAL 1664 EQUAL Reactome Database ID Release 82 1983670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1983670 Reactome R-HSA-1983670 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1983670.1 1 NOTCH1(1665-2555) NOTCH1 Transmembrane fragment (NTMIC1) Reactome DB_ID: 157239 1665 EQUAL 2555 EQUAL Reactome Database ID Release 82 157239 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157239 Reactome R-HSA-157239 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157239.1 1 Reactome Database ID Release 82 157027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157027 Reactome R-HSA-157027 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157027.1 Fringe-modified NOTCH1 Glu,Sia-Gal-GlcNAc-Fuc-NOTCH1 Reactome DB_ID: 1911516 1 Sia-Gal-GlcNAc-NECD1 FRINGE-modified NOTCH1 Extracellular Fragment (NECD1) Reactome DB_ID: 1911512 19 EQUAL 1664 EQUAL Reactome Database ID Release 82 1911512 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911512 Reactome R-HSA-1911512 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911512.1 1 Reactome Database ID Release 82 1911516 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911516 Reactome R-HSA-1911516 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911516.1 Reactome Database ID Release 82 1911555 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911555 Reactome R-HSA-1911555 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911555.1 DLL4:NOTCH1 Reactome DB_ID: 1911559 1 1 Reactome Database ID Release 82 1911559 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911559 Reactome R-HSA-1911559 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911559.1 Reactome Database ID Release 82 1980041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980041 Reactome R-HSA-1980041 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980041.1 19524514 Pubmed 2009 The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis Benedito, R Roca, C Sörensen, I Adams, S Gossler, A Fruttiger, M Adams, Ralf H Cell 137:1124-35 18824585 Pubmed 2008 Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment Koch, U Fiorini, E Benedito, R Besseyrias, V Schuster-Gossler, K Pierres, M Manley, NR Duarte, A MacDonald, HR Radtke, F J Exp Med 205:2515-23 18824583 Pubmed 2008 Delta-like 4 is indispensable in thymic environment specific for T cell development Hozumi, K Mailhos, C Negishi, N Hirano, K Yahata, T Ando, K Zuklys, S Holländer, GA Shima, DT Habu, S J Exp Med 205:2507-13