BioPAX pathway converted from "NOTCH3 binds DLL4" in the Reactome database. LEFT-TO-RIGHT NOTCH3 binds DLL4 Binding of NOTCH3 receptor to DLL4 ligand has not been directly demonstrated. DLL4 and NOTCH3 are expressed on neighboring cells in retina (Claxton and Fruttiger 2004) and in endothelium/blood (Indraccolo et al. 2009), and DLL4 significantly and specifically increases NOTCH3 signaling (Indraccolo et al. 2009). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 NOTCH3 NTM-NEC 3 heterodimer Reactome DB_ID: 157048 plasma membrane GENE ONTOLOGY GO:0005886 NOTCH3 Extracellular fragment (NECD3) 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) Reactome DB_ID: 1983675 extracellular region GENE ONTOLOGY GO:0005576 UniProt:Q9UM47 NOTCH3 NOTCH3 FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination (PubMed:15350543). 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 (By similarity).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with PSMA1. Interacts with HIF1AN.TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.DOMAIN The EGF-like domains 10 and 11 are required for binding the ligands JAG1 and DLL1.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. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.PTM Hydroxylated by HIF1AN.SIMILARITY Belongs to the NOTCH family. Homo sapiens NCBI Taxonomy 9606 UniProt Q9UM47 173 EQUAL O-fucosyl-L-threonine MOD MOD:00813 211 EQUAL 250 EQUAL 290 EQUAL 328 EQUAL 445 EQUAL 671 EQUAL O-fucosyl-L-serine MOD MOD:00812 748 EQUAL 863 EQUAL 938 EQUAL 1098 EQUAL 1136 EQUAL 1181 EQUAL 1349 EQUAL 84 EQUAL O-glucosyl-L-serine MOD MOD:00804 125 EQUAL 357 EQUAL 437 EQUAL 475 EQUAL 513 EQUAL 588 EQUAL 626 EQUAL 663 EQUAL 740 EQUAL 893 EQUAL 968 EQUAL 1128 EQUAL 1252 EQUAL 40 EQUAL 1571 EQUAL Reactome Database ID Release 82 1983675 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=1983675 Reactome R-HSA-1983675 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-1983675.1 Reactome http://www.reactome.org 1 NOTCH3(1572-2321) Notch3 Transmembrane fragment (NTMIC3) Reactome DB_ID: 157231 1572 EQUAL 2321 EQUAL Reactome Database ID Release 82 157231 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=157231 Reactome R-HSA-157231 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-157231.1 1 Reactome Database ID Release 82 157048 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=157048 Reactome R-HSA-157048 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-157048.1 DLL4 Delta 4 ligand Reactome DB_ID: 158437 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. 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 DLL4:NOTCH3 Reactome DB_ID: 2168132 1 1 Reactome Database ID Release 82 2168132 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=2168132 Reactome R-HSA-2168132 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-2168132.1 Reactome Database ID Release 82 2168136 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=2168136 Reactome R-HSA-2168136 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-2168136.1 15533827 Pubmed 2004 Periodic Delta-like 4 expression in developing retinal arteries Claxton, S Fruttiger, M Gene Expr Patterns 5:123-7 19208840 Pubmed 2009 Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy Indraccolo, S Minuzzo, S Masiero, M Pusceddu, I Persano, L Moserle, L Reboldi, A Favaro, E Mecarozzi, M Di Mario, G Screpanti, I Ponzoni, M Doglioni, C Amadori, A Cancer Res 69:1314-23 GENE ONTOLOGY GO:0007219 gene ontology term for cellular process MI MI:0359