BioPAX pathway converted from "NOTCH3 binds DLL4" in the Reactome database. NOTCH3 binds DLL4 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 Reactome DB_ID: 157048 1 plasma membrane GO 0005886 NOTCH3 [plasma membrane] NOTCH3 NTM-NEC 3 heterodimer Reactome DB_ID: 1983675 1 extracellular region GO 0005576 UniProt:Q9UM47 NOTCH3 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. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q9UM47 O-fucosyl-L-threonine at 173 173 EQUAL O-fucosyl-L-threonine O-fucosyl-L-threonine at 211 211 EQUAL O-fucosyl-L-threonine at 250 250 EQUAL O-fucosyl-L-threonine at 290 290 EQUAL O-fucosyl-L-threonine at 328 328 EQUAL O-fucosyl-L-threonine at 445 445 EQUAL O-fucosyl-L-serine at 671 671 EQUAL O-fucosyl-L-serine O-fucosyl-L-threonine at 748 748 EQUAL O-fucosyl-L-serine at 863 863 EQUAL O-fucosyl-L-threonine at 938 938 EQUAL O-fucosyl-L-threonine at 1098 1098 EQUAL O-fucosyl-L-serine at 1136 1136 EQUAL O-fucosyl-L-threonine at 1181 1181 EQUAL O-fucosyl-L-serine at 1349 1349 EQUAL O-glucosyl-L-serine at 84 84 EQUAL O-glucosyl-L-serine O-glucosyl-L-serine at 125 125 EQUAL O-glucosyl-L-serine at 357 357 EQUAL O-glucosyl-L-serine at 437 437 EQUAL O-glucosyl-L-serine at 475 475 EQUAL O-glucosyl-L-serine at 513 513 EQUAL O-glucosyl-L-serine at 588 588 EQUAL O-glucosyl-L-serine at 626 626 EQUAL O-glucosyl-L-serine at 663 663 EQUAL O-glucosyl-L-serine at 740 740 EQUAL O-glucosyl-L-serine at 893 893 EQUAL O-glucosyl-L-serine at 968 968 EQUAL O-glucosyl-L-serine at 1128 1128 EQUAL O-glucosyl-L-serine at 1252 1252 EQUAL Chain Coordinates 40 EQUAL 1571 EQUAL Reactome DB_ID: 157231 1 1572 EQUAL 2321 EQUAL 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 Reactome DB_ID: 158437 1 UniProt:Q9NR61 DLL4 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 DB_ID: 2168132 1 DLL4:NOTCH3 [plasma membrane] DLL4:NOTCH3 Reactome DB_ID: 157048 1 Reactome DB_ID: 158437 1 27 EQUAL 685 EQUAL 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 GO 0007219 GO biological process