BioPAX pathway converted from "NOTCH3 Activation and Transmission of Signal to the Nucleus" in the Reactome database. NOTCH3 Activation and Transmission of Signal to the Nucleus NOTCH3 Activation and Transmission of Signal to the Nucleus NOTCH3 receptor can be activated by DLL/JAG ligands DLL1, JAG1, and JAG2 (Shimizu et al. 2000), as well as DLL4 (Claxton and Fruttiger 2004, Indraccolo et al. 2009). Ligand binding induces a conformational change in NOTCH3, which exposes the S2 site in the extracellular region of NOTCH3. The S2 site is cleaved by ADAM10 metalloprotease, generating the membrane anchored NOTCH3 fragment NEXT3. The NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma secretase complex, releasing the intracellular domain NICD3 into the cytosol (Groot et al. 2014). Besides DLL/JAG ligands, NOTCH3 signaling can also be activated by binding of NOTCH3 to YBX1 (YB 1) (Rauen et al. 2009). NICD3 traffics to the nucleus where it acts as a transcription factor. WWP2, an E3 ubiquitin ligase, negatively regulates NOTCH3 signaling by ubiquitinating NEXT3 and NICD3 in the cytosol and targeting them for lysosome-mediated degradation (Jung et al. 2014). NOTCH3 signaling is also negatively regulated by binding to TACC3 (Bargo et al. 2010) and by EGFR-mediated phosphorylation (Arasada et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 NOTCH3 binds DLL1 NOTCH3 binds DLL1 Based on a study with mouse proteins, NOTCH3 receptor binds to DLL1 ligand (Shimizu et al. 2000). The interaction of DLL1 and NOTCH3 is implicated in functional differentiation of activated CD4+ T lymphocytes into type 1 helper T cells (Th1) (Maekawa et al. 2003). The effect of Fringe-mediated modification of NOTCH3 on its interaction with DLL1 is poorly studied (Hou et al. 2012). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157089 1 plasma membrane GO 0005886 UniProt:O00548 DLL1 DLL1 UNQ146/PRO172 DLL1 FUNCTION Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity).SUBUNIT Homodimer. Interacts with TJP1. Interacts with MAGI1 (via PDZ domain); forms a complex with CTNNB1 and CDH2 and promotes recruitment to the adherens junction and stabilization on the cell surface. Interacts with PSEN1; undergoes a presenilin-dependent gamma-secretase cleavage that releases a Dll1-intracellular form. Interacts with MFAP5. Interacts with MIB1. Interacts with NEURL1B; leads to ubiquitination. Interacts with NEURL1 (By similarity). Interacts with SYNJ2BP; enhances DLL1 protein stability, and promotes Notch signaling in endothelial cells (PubMed:24025447). Interacts with MAGI1, MAGI2, MAGI3 and MPDZ (PubMed:15509766). Interacts (via ubiquitin) with EPN1 (via IUM domain); binding with NOTCH1 attached to neighboring cell, promotes ligand ubiquitination and EPN1 interaction, leading to NECD transendocytosis and Notch signaling. Interacts with NOTCH1 (By similarity) (PubMed:15509766, PubMed:24025447). Interacts with NOTCH2NLB; leading to promote Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions (PubMed:29856955).TISSUE SPECIFICITY Expressed in heart and pancreas, with lower expression in brain and muscle and almost no expression in placenta, lung, liver and kidney.PTM Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation (By similarity). Ubiquitinated; promotes recycling back to the plasma membrane and confers a strong affinity for NOTCH1. Multi-ubiquitination of LYS-613 by MIB1 promotes both cis and trans-interaction with NOTCH1, as well as activation of Notch signaling. Ubiquitinated by NEURL1B (By similarity).PTM Phosphorylated in a membrane association-dependent manner. Phosphorylation at Ser-697 requires the presence of Ser-694, whereas phosphorylation at Ser-694 occurs independently of the other site. Phosphorylation is required for full ligand activity in vitro and affects surface presentation, ectodomain shedding, and endocytosis.PTM O-fucosylated. Can be elongated to a disaccharide by MFNG. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt O00548 Chain Coordinates 18 EQUAL 723 EQUAL Reactome DB_ID: 157048 1 NOTCH3 [plasma membrane] NOTCH3 NTM-NEC 3 heterodimer Reactome DB_ID: 157231 1 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. UniProt Q9UM47 1572 EQUAL 2321 EQUAL Reactome DB_ID: 1983675 1 extracellular region GO 0005576 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 40 EQUAL 1571 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: 157136 1 DLL1:NOTCH3 [plasma membrane] DLL1:NOTCH3 Reactome DB_ID: 157089 1 18 EQUAL 723 EQUAL Reactome DB_ID: 157048 1 Reactome Database ID Release 82 157136 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=157136 Reactome R-HSA-157136 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-157136.1 Reactome Database ID Release 82 157145 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=157145 Reactome R-HSA-157145 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-157145.1 14563319 Pubmed 2003 Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells Maekawa, Yoichi Tsukumo, Shin-ichi Chiba, Shigeru Hirai, Hisamaru Hayashi, Yuki Okada, Hiroko Kishihara, Kenji Yasutomo, Koji Immunity 19:549-59 22081605 Pubmed 2012 Galactose differentially modulates lunatic and manic fringe effects on Delta1-induced NOTCH signaling Hou, Xinghua Tashima, Y Stanley, P J. Biol. Chem. 287:474-83 11006133 Pubmed 2000 Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors Shimizu, K Chiba, S Saito, T Kumano, K Hirai, H Biochem Biophys Res Commun 276:385-9 GO 0007219 GO biological process NOTCH3 binds JAG1 NOTCH3 binds JAG1 Based on a study with mouse proteins, NOTCH3 receptor binds to JAG1 (Jagged1) ligand (Shimizu et al. 1999). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157098 1 UniProt:P78504 JAG1 JAG1 JAG1 JAGL1 FUNCTION Ligand for multiple Notch receptors and involved in the mediation of Notch signaling (PubMed:18660822, PubMed:20437614). May be involved in cell-fate decisions during hematopoiesis (PubMed:9462510). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).SUBUNIT Interacts with NOTCH2 and NOTCH3 (By similarity). Interacts with NOTCH1 (in the presence of calcium ions) (PubMed:18660822).TISSUE SPECIFICITY Widely expressed in adult and fetal tissues. In cervix epithelium expressed in undifferentiated subcolumnar reserve cells and squamous metaplasia. Expression is up-regulated in cervical squamous cell carcinoma. Expressed in bone marrow cell line HS-27a which supports the long-term maintenance of immature progenitor cells.DEVELOPMENTAL STAGE Expressed in 32-52 days embryos in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube.DOMAIN The second EGF-like domain is atypical. UniProt P78504 34 EQUAL 1218 EQUAL Reactome DB_ID: 157048 1 Reactome DB_ID: 157132 1 JAG1:NOTCH3 [plasma membrane] JAG1:NOTCH3 Reactome DB_ID: 157098 1 34 EQUAL 1218 EQUAL Reactome DB_ID: 157048 1 Reactome Database ID Release 82 157132 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=157132 Reactome R-HSA-157132 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-157132.1 Reactome Database ID Release 82 157100 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=157100 Reactome R-HSA-157100 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-157100.1 10079256 Pubmed 1999 Human ligands of the Notch receptor Gray, GE Mann, RS Mitsiadis, E Henrique, D Carcangiu, ML Banks, A Leiman, J Ward, D Ish-Horowitz, D Artavanis-Tsakonas, S Am J Pathol 154:785-94 NOTCH3 binds JAG2 NOTCH3 binds JAG2 Based on a study with mouse NOTCH3 and presumably mouse JAG2 (Jagged2), JAG2 ligand binds to NOTCH3 receptor (Shimizu et al. 2000). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157120 1 UniProt:Q9Y219 JAG2 JAG2 JAG2 FUNCTION Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development (By similarity).TISSUE SPECIFICITY Expressed in heart, placenta and skeletal muscle and to a lesser extent in pancreas. Very low expression in brain, lung, liver and kidney. UniProt Q9Y219 24 EQUAL 1238 EQUAL Reactome DB_ID: 157048 1 Reactome DB_ID: 157066 1 JAG2:NOTCH3 [plasma membrane] JAG2:NOTCH3 Reactome DB_ID: 157120 1 24 EQUAL 1238 EQUAL Reactome DB_ID: 157048 1 Reactome Database ID Release 82 157066 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=157066 Reactome R-HSA-157066 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-157066.1 Reactome Database ID Release 82 157124 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=157124 Reactome R-HSA-157124 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-157124.1 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: 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: 157048 1 Reactome DB_ID: 2168132 1 DLL4:NOTCH3 [plasma membrane] DLL4:NOTCH3 Reactome DB_ID: 158437 1 27 EQUAL 685 EQUAL Reactome DB_ID: 157048 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 6.3.2.19 Ubiquitination of DLL/JAG ligands upon binding to NOTCH3 Ubiquitination of DLL/JAG ligands upon binding to NOTCH3 Based on an analogy with NOTCH1 and NOTCH2, and on studies of Drosophila Notch, NOTCH ligands DLL1, DLL4, JAG1 and JAG2 are assumed to undergo ubiquitination and endocytosis after binding to NOTCH3 in trans. Ubiquitination of DLL/JAG ligands in mammals is performed by orthologues of Drosophila Mindbomb, MIB1, possibly MIB2, and possibly orthologues of Drosophila Neuralized, NEURL and NEURL1B. Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Converted from EntitySet in Reactome Reactome DB_ID: 113595 3 cytosol GO 0005829 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBA52(1-76) [cytosol] UBC(533-608) [cytosol] UBC(153-228) [cytosol] UBC(77-152) [cytosol] UBC(305-380) [cytosol] UBC(381-456) [cytosol] UBC(457-532) [cytosol] UBC(609-684) [cytosol] UBC(1-76) [cytosol] UBB(1-76) [cytosol] UBC(229-304) [cytosol] UBB(153-228) [cytosol] RPS27A(1-76) [cytosol] UBB(77-152) [cytosol] UniProt P62987 UniProt P0CG48 UniProt P0CG47 UniProt P62979 Converted from EntitySet in Reactome Reactome DB_ID: 9013071 1 DLL/JAG:NOTCH3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 9013089 1 Ub-DLL/JAG:NOTCH3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1911464 MIB/NEURL [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MIB1 [cytosol] UniProt Q86YT6 GO 0004842 GO molecular function Reactome Database ID Release 82 1980072 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=1980072 Reactome Database ID Release 82 9013069 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=9013069 Reactome R-HSA-9013069 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-9013069.1 NOTCH3-ligand complex is cleaved to produce NEXT3 NOTCH3-ligand complex is cleaved to produce NEXT3 Ligand binding induces a conformational change in NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of the receptor-attached ubiquitinated ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and triggers cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3 (Groot et al. 2014). The extracellular NOTCH3 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Converted from EntitySet in Reactome Reactome DB_ID: 9013089 1 Converted from EntitySet in Reactome Reactome DB_ID: 9013287 1 Ub-DLL/JAG:NOTCH3(40-1628) [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 157203 1 1629 EQUAL 2321 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157186 ADAM10:Zn2+ [plasma membrane] ADAM10:Zn2+ ADAM 10 metalloprotease (Zn cofactor) Reactome DB_ID: 157237 1 UniProt:O14672 ADAM10 ADAM10 KUZ ADAM10 MADM FUNCTION Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).FUNCTION (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.ACTIVITY REGULATION Catalytically inactive when the propeptide is intact and associated with the mature enzyme (By similarity). The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates (PubMed:29224781).SUBUNIT Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells (PubMed:16239146). Interacts with the clathrin adapter AP2 complex subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with TSPAN33 (via extracellular domain) and (via cytoplasmic domain) with AFDN; interaction with TSPAN33 allows the docking of ADAM10 to zonula adherens through a PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while interaction with AFDN locks ADAM10 at zonula adherens (PubMed:30463011). Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions (By similarity). Interacts with EPHA2 (By similarity). Interacts with NGF in a divalent cation-dependent manner (PubMed:20164177). Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression (PubMed:26686862, PubMed:26668317). Interacts with TSPAN5, TSPAN10, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity (PubMed:26686862). Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with BACE1 (via extracellular domain) (By similarity). Interacts with FAM171A1 (PubMed:30312582).SUBUNIT (Microbial infection) Interacts with S.aureus hly; this interaction is necessary for toxin pore formation, disruption of focal adhesions and S.aureus hly-mediated cytotoxicity.TISSUE SPECIFICITY Expressed in the brain (at protein level) (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver (PubMed:11511685, PubMed:9016778).INDUCTION In osteoarthritis affected-cartilage.DOMAIN The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.DOMAIN The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins (By similarity). Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is sufficient for interaction with TSPAN15 (By similarity).PTM The precursor is cleaved by furin and PCSK7. UniProt O14672 214 EQUAL 748 EQUAL Reactome DB_ID: 109265 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome Database ID Release 82 157186 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=157186 Reactome R-HSA-157186 2 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-157186.2 GO 0008237 GO molecular function Reactome Database ID Release 82 157208 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=157208 Reactome Database ID Release 82 9013284 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=9013284 Reactome R-HSA-9013284 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-9013284.1 24842903 Pubmed 2014 Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins Groot, Arjan J Habets, Roger Yahyanejad, Sanaz Hodin, Caroline M Reiss, Karina Saftig, P Theys, Jan Vooijs, M Mol. Cell. Biol. 34:2822-32 GO 0035333 GO biological process 3.4.23.32 3.4.23.43 3.4.23.20 3.4.23.25 3.4.23.36 3.4.23.35 3.4.23.34 3.4.23.4 3.4.23.5 3.4.23.1 3.4.23.15 NEXT3 is cleaved to produce NICD3 NEXT3 is cleaved to produce NICD3 NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma-secretase complex, containing either PSEN1 (presenilin-1) or PSEN2 (presenilin-2) as the catalytic subunit, which releases the intracellular domain NICD3 into the cytosol (Groot et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157203 1 1629 EQUAL 2321 EQUAL Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 157657 1 1629 EQUAL 1661 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157343 gamma-secretase complex [plasma membrane] gamma-secretase complex Converted from EntitySet in Reactome Reactome DB_ID: 9013333 1 Presenilin [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 157331 1 UniProt:Q9NZ42 PSENEN PSENEN PSENEN PEN2 MDS033 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).SUBUNIT The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN.TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.SIMILARITY Belongs to the PEN-2 family.CAUTION The high-resolution electron microscopy structures indicate that the N-terminus is cytoplasmic, followed by two short helices that dip into the membrane, but do not cross it (PubMed:26280335). In contrast, results based on mutagenesis to create N-glycosylation sites indicate that the N-terminus is lumenal (PubMed:12639958, PubMed:30598546, PubMed:30630874). Both studies indicate that the C-terminus is lumenal (PubMed:12639958, PubMed:26280335). UniProt Q9NZ42 1 EQUAL 101 EQUAL Reactome DB_ID: 2534241 1 UniProt:Q92542 NCSTN NCSTN NCSTN KIAA0253 UNQ1874/PRO4317 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.SUBUNIT Component of the gamma-secretase complex (PubMed:10993067, PubMed:30598546, PubMed:30630874). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:25918421, PubMed:30598546, PubMed:30630874). Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (PubMed:10993067, PubMed:30630874). Interacts with PSEN1 and PSEN2 (PubMed:10993067).TISSUE SPECIFICITY Detected in brain (at protein level) (PubMed:10993067). Widely expressed (PubMed:11396676).INDUCTION Constitutively expressed in neural cells.PTM N-glycosylated.SIMILARITY Belongs to the nicastrin family. UniProt Q92542 34 EQUAL 709 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 157341 1 APH-1 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity APH1B [plasma membrane] APH1A [plasma membrane] UniProt Q8WW43 UniProt Q96BI3 Reactome Database ID Release 82 157343 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=157343 Reactome R-HSA-157343 2 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-157343.2 GO 0004190 GO molecular function Reactome Database ID Release 82 157355 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=157355 Reactome Database ID Release 82 9013361 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=9013361 Reactome R-HSA-9013361 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-9013361.1 Noncanonical activation of NOTCH3 Noncanonical activation of NOTCH3 Besides DLL/JAG ligands, NOTCH3 signaling can also be activated by binding of NOTCH3 to YBX1 (YB 1) (Rauen et al. 2009). YBX1, a protein involved in mRNA processing, is secreted by mesangial cells and monocytes during inflammation and acts as an extracellular mitogen (Frye et al. 2009). YBX1 triggers the gamma secretase complex mediated cleavage of NOTCH3, resulting in release of NOTCH3 intracellular domain (NICD3) and activation of NOTCH3 target genes (Rauen et al. 2009). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 NOTCH3 binds YBX1 NOTCH3 binds YBX1 YBX1 (YB-1) binds to EGF repeats in the extracellular domain of NOTCH3 (Rauen et al. 2009). While YBX1 is extensively studied as a protein involved in mRNA processing, it is also secreted by mesangial cells and monocytes during inflammation and can act as an extracellular mitogen (Frye 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: 9017791 1 UniProt:P67809 YBX1 YBX1 NSEP1 YB1 YBX1 FUNCTION DNA- and RNA-binding protein involved in various processes, such as translational repression, RNA stabilization, mRNA splicing, DNA repair and transcription regulation (PubMed:8188694, PubMed:10817758, PubMed:11698476, PubMed:14718551, PubMed:18809583, PubMed:31358969). Predominantly acts as a RNA-binding protein: binds preferentially to the 5'-[CU]CUGCG-3' RNA motif and specifically recognizes mRNA transcripts modified by C5-methylcytosine (m5C) (PubMed:19561594, PubMed:31358969). Promotes mRNA stabilization: acts by binding to m5C-containing mRNAs and recruiting the mRNA stability maintainer ELAVL1, thereby preventing mRNA decay (PubMed:10817758, PubMed:11698476, PubMed:31358969). Component of the CRD-mediated complex that promotes MYC mRNA stability (PubMed:19029303). Contributes to the regulation of translation by modulating the interaction between the mRNA and eukaryotic initiation factors (By similarity). Plays a key role in RNA composition of extracellular exosomes by defining the sorting of small non-coding RNAs, such as tRNAs, Y RNAs, Vault RNAs and miRNAs (PubMed:27559612, PubMed:29073095). Probably sorts RNAs in exosomes by recognizing and binding C5-methylcytosine (m5C)-containing RNAs (PubMed:28341602, PubMed:29073095). Acts as a key effector of epidermal progenitors by preventing epidermal progenitor senescence: acts by regulating the translation of a senescence-associated subset of cytokine mRNAs, possibly by binding to m5C-containing mRNAs (PubMed:29712925). Also involved in pre-mRNA alternative splicing regulation: binds to splice sites in pre-mRNA and regulates splice site selection (PubMed:12604611). Also able to bind DNA: regulates transcription of the multidrug resistance gene MDR1 is enhanced in presence of the APEX1 acetylated form at 'Lys-6' and 'Lys-7' (PubMed:18809583). Binds to promoters that contain a Y-box (5'-CTGATTGGCCAA-3'), such as MDR1 and HLA class II genes (PubMed:8188694, PubMed:18809583). Promotes separation of DNA strands that contain mismatches or are modified by cisplatin (PubMed:14718551). Has endonucleolytic activity and can introduce nicks or breaks into double-stranded DNA, suggesting a role in DNA repair (PubMed:14718551). The secreted form acts as an extracellular mitogen and stimulates cell migration and proliferation (PubMed:19483673).SUBUNIT Homodimer in the presence of ATP (PubMed:10817758, PubMed:11851341). Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1 (PubMed:19029303). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077). Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1 (By similarity). Interacts with IGF2BP1 and RBBP6 (PubMed:17289661, PubMed:18851979). Component of cytoplasmic messenger ribonucleoprotein particles (mRNPs) (PubMed:19029303). Interacts with AKT1, MBNL1, SFRS9, SFRS12, ALYREF/THOC4, MSH2, XRCC5, WRN and NCL (PubMed:12604611, PubMed:14559993, PubMed:14718551, PubMed:15806160, PubMed:18335541). Interacts (via C-terminus) with APEX1 (via N-terminus); the interaction is increased with APEX1 acetylated at 'Lys-6' and 'Lys-7' (PubMed:18809583). Interacts with AGO1 and AGO2 (PubMed:17932509). Interacts with ANKRD2 (PubMed:15136035). Interacts with DERA (PubMed:25229427). Interacts with FMR1; this interaction occurs in association with polyribosome (By similarity). Interacts with ZBTB7B (By similarity). Interacts with HDGF (isoform 1) (PubMed:26845719). Interacts with ELAVL1; leading to ELAVL1 recruitment on C5-methylcytosine (m5C)-containing mRNAs and subsequent mRNA stability (PubMed:31358969).DOMAIN In the CSD domain, Trp-65 specifically recognizes C5-methylcytosine (m5C) modification through its indole ring.PTM Ubiquitinated by RBBP6; leading to a decrease of YBX1 transcactivational ability.PTM In the absence of phosphorylation the protein is retained in the cytoplasm.PTM Cleaved by a 20S proteasomal protease in response to agents that damage DNA. Cleavage takes place in the absence of ubiquitination and ATP. The resulting N-terminal fragment accumulates in the nucleus (By similarity).SIMILARITY Belongs to the YBX1 family. UniProt P67809 2 EQUAL 324 EQUAL Reactome DB_ID: 157048 1 Reactome DB_ID: 9017807 1 YBX1:NOTCH3 [plasma membrane] YBX1:NOTCH3 Reactome DB_ID: 9017791 1 2 EQUAL 324 EQUAL Reactome DB_ID: 157048 1 Reactome Database ID Release 82 9017807 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=9017807 Reactome R-HSA-9017807 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-9017807.1 Reactome Database ID Release 82 9017797 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=9017797 Reactome R-HSA-9017797 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-9017797.1 19640841 Pubmed 2009 YB-1 acts as a ligand for Notch-3 receptors and modulates receptor activation Rauen, Thomas Raffetseder, U Frye, Björn C Djudjaj, Sonja Mühlenberg, Philipp J T Eitner, Frank Lendahl, U Bernhagen, Jürgen Dooley, Steven Mertens, Peter R J. Biol. Chem. 284:26928-40 19483673 Pubmed 2009 Y-box protein-1 is actively secreted through a non-classical pathway and acts as an extracellular mitogen Frye, Björn C Halfter, Sarah Djudjaj, Sonja Muehlenberg, Philipp Weber, Susanne Raffetseder, U En-Nia, Abdelaziz Knott, Hanna Baron, Jens M Dooley, Steven Bernhagen, Jürgen Mertens, Peter R EMBO Rep. 10:783-9 3.4.23.32 3.4.23.43 3.4.23.20 3.4.23.25 3.4.23.36 3.4.23.35 3.4.23.34 3.4.23.4 3.4.23.5 3.4.23.1 3.4.23.15 Gamma-secretase cleaves YBX1:NOTCH3 Gamma-secretase cleaves YBX1:NOTCH3 Binding of NOTCH3 to YBX1 (YB-1) triggers cleavage of NOTCH3 by the gamma-secretase complex. The exact steps of YBX1-mediated NOTCH3 activation are not known. The gamma-secretase complex releases NOTCH3 intracellular domain (NICD3), leading to activation of NOTCH3 target genes downstream of YBX1 (Rauen 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: 9017807 1 Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157343 Reactome Database ID Release 82 9017817 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=9017817 Reactome R-HSA-9017817 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-9017817.1 Reactome Database ID Release 82 9017802 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=9017802 Reactome R-HSA-9017802 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-9017802.1 NICD3 binds to TACC3 NICD3 binds to TACC3 Based on studies in mice, the intracellular domain of NOTCH3, NICD3, binds to transforming acidic coiled-coil protein-3 (TACC3). The interaction involves the ankyrin repeats of NOTCH3. The two proteins co-localize in the cytosol and possibly in the nucleus. TACC3 is implicated as a negative regulator of NOTCH signaling and may compete with NOTCH binding to RPBJ (Bargo et al. 2010). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 2160956 1 UniProt:Q9Y6A5 TACC3 TACC3 TACC3 ERIC1 FUNCTION Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors (By similarity). Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:21297582, PubMed:23532825). May be involved in the control of cell growth and differentiation. May contribute to cancer (PubMed:14767476).SUBUNIT Interacts with microtubules. Interacts with CKAP5 independently of clathrin. Interacts with CKAP5 and clathrin forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges; TACC3 (phosphorylated at Ser-558 by AURKA) and CLTC are proposed to form a composite microtubule interaction surface (PubMed:21297582, PubMed:23918938, PubMed:25596274). Interacts with CCDC100/CEP120. The coiled coil C-terminal region interacts with AH receptor nuclear translocator protein (ARNT) and ARNT2 (By similarity). Interacts with GCN5L2 and PCAF (PubMed:14767476).INDUCTION Up-regulated in various cancer cell lines.SIMILARITY Belongs to the TACC family. UniProt Q9Y6A5 1 EQUAL 838 EQUAL Reactome DB_ID: 9017852 1 NICD3:TACC3 [cytosol] NICD3:TACC3 Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 2160956 1 1 EQUAL 838 EQUAL Reactome Database ID Release 82 9017852 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=9017852 Reactome R-HSA-9017852 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-9017852.1 Reactome Database ID Release 82 9017855 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=9017855 Reactome R-HSA-9017855 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-9017855.1 20804727 Pubmed 2010 Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats Bargo, Sharon Raafat, Ahmed McCurdy, David Amirjazil, Idean Shu, Youmin Traicoff, June Plant, Joshua Vonderhaar, Barbara K Callahan, Robert Biochem. Biophys. Res. Commun. 400:606-12 GO 0045746 GO biological process NOTCH3 binds activated EGFR NOTCH3 binds activated EGFR The intracellular domain of NOTCH3 (NICD3) co-immunoprecipitates with ligand activated, autophosphorylated EGFR. Binding of NOTCH3 to EGFR is inhibited by erlotinib treatment, which prevents EGFR activation (Arasada et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 179882 1 EGF:p-6Y-EGFR dimer [plasma membrane] EGF:p-6Y-EGFR dimer EGF:Phospho-EGFR (Y992, Y1068, Y1086, Y1148, Y1173) dimer Reactome DB_ID: 179860 2 EGF:Phospho-EGFR [plasma membrane] EGF:Phospho-EGFR Reactome DB_ID: 179803 1 UniProt:P00533 EGFR EGFR ERBB1 ERBB HER1 EGFR FUNCTION Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:2790960, PubMed:10805725, PubMed:27153536). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975, PubMed:15611079, PubMed:12297049, PubMed:27153536, PubMed:20837704, PubMed:17909029). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity).FUNCTION Isoform 2 may act as an antagonist of EGF action.FUNCTION (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.ACTIVITY REGULATION Endocytosis and inhibition of the activated EGFR by phosphatases like PTPRJ and PTPRK constitute immediate regulatory mechanisms. Upon EGF-binding phosphorylates EPS15 that regulates EGFR endocytosis and activity. Moreover, inducible feedback inhibitors including LRIG1, SOCS4, SOCS5 and ERRFI1 constitute alternative regulatory mechanisms for the EGFR signaling. Up-regulated by NEU3-mediated desialylation of N-linked glycan at Asn-528.SUBUNIT Binding of the ligand triggers homo- and/or heterodimerization of the receptor triggering its autophosphorylation. Heterodimer with ERBB2 (PubMed:10805725). Forms a complex with CCDC88A/GIV (via SH2-like regions) and GNAI3 which leads to enhanced EGFR signaling and triggering of cell migration; binding to CCDC88A requires autophosphorylation of the EGFR C-terminal region, and ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955, PubMed:25187647). Interacts with ERRFI1; inhibits dimerization of the kinase domain and autophosphorylation (PubMed:18046415). Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B (PubMed:10805725). Interacts with GRB2; an adapter protein coupling the receptor to downstream signaling pathways. Interacts with GAB2; involved in signaling downstream of EGFR. Interacts with STAT3; mediates EGFR downstream signaling in cell proliferation. Interacts with RIPK1; involved in NF-kappa-B activation. Interacts (autophosphorylated) with CBL, CBLB and CBLC; involved in EGFR ubiquitination and regulation. Interacts with SOCS5; regulates EGFR degradation through ELOC- and ELOB-mediated ubiquitination and proteasomal degradation. Interacts with PRMT5; methylates EGFR and enhances interaction with PTPN6. Interacts (phosphorylated) with PTPN6; inhibits EGFR-dependent activation of MAPK/ERK. Interacts with COPG1; essential for regulation of EGF-dependent nuclear transport of EGFR by retrograde trafficking from the Golgi to the ER. Interacts with TNK2; this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts with PCNA; positively regulates PCNA (PubMed:17115032). Interacts with PELP1. Interacts with MUC1. Interacts with AP2M1. Interacts with FER. May interact with EPS8; mediates EPS8 phosphorylation. Interacts (via SH2 domains) with GRB2, NCK1 and NCK2 (PubMed:10026169). Interacts with ATXN2. Interacts with GAREM1. Interacts (ubiquitinated) with ANKRD13A/B/D; the interaction is direct and may regulate EGFR internalization after EGF stimulation. Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts (via C-terminal cytoplasmic kinase domain) with ZPR1 (via zinc fingers). Interacts with RNF115 and RNF126 (PubMed:23418353). Interacts with GPRC5A (via its transmembrane domain) (PubMed:25311788). Interacts with FAM83B; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (PubMed:23912460). Interacts with LAPTM4B; positively correlates with EGFR activation (PubMed:28479384). Interacts with STX19 (PubMed:16420529). Interacts with CD44 (PubMed:23589287). Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization (PubMed:26988023). Interacts with PIKFYVE (PubMed:17909029). Interacts with NEU3. Interacts with TRAF4 (PubMed:30352854).TISSUE SPECIFICITY Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers.PTM Phosphorylated on Tyr residues in response to EGF (PubMed:20462955, PubMed:27153536). Phosphorylation at Ser-695 is partial and occurs only if Thr-693 is phosphorylated. Phosphorylation at Thr-678 and Thr-693 by PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the receptor at the plasma membrane. Autophosphorylation at Tyr-1197 is stimulated by methylation at Arg-1199 and enhances interaction with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 recruits STAT3. Dephosphorylated by PTPN1 and PTPN2.PTM Monoubiquitinated and polyubiquitinated upon EGF stimulation; which does not affect tyrosine kinase activity or signaling capacity but may play a role in lysosomal targeting (PubMed:27153536). Polyubiquitin linkage is mainly through 'Lys-63', but linkage through 'Lys-48', 'Lys-11' and 'Lys-29' also occurs. Deubiquitination by OTUD7B prevents degradation. Ubiquitinated by RNF115 and RNF126 (By similarity).PTM Palmitoylated on Cys residues by ZDHHC20. Palmitoylation inhibits internalization after ligand binding, and increases the persistence of tyrosine-phosphorylated EGFR at the cell membrane. Palmitoylation increases the amplitude and duration of EGFR signaling.PTM Methylated. Methylation at Arg-1199 by PRMT5 stimulates phosphorylation at Tyr-1197.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. UniProt P00533 O4'-phospho-L-tyrosine at 992 992 EQUAL O4'-phospho-L-tyrosine [MOD:00048] O4'-phospho-L-tyrosine at 1045 1045 EQUAL O4'-phospho-L-tyrosine at 1068 1068 EQUAL O4'-phospho-L-tyrosine at 1086 1086 EQUAL O4'-phospho-L-tyrosine at 1148 1148 EQUAL O4'-phospho-L-tyrosine at 1173 1173 EQUAL 25 EQUAL 1210 EQUAL Reactome DB_ID: 179863 1 UniProt:P01133 EGF EGF EGF FUNCTION EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in the renal distal convoluted tubule via engagement of EGFR and activation of the magnesium channel TRPM6. Can induce neurite outgrowth in motoneurons of the pond snail Lymnaea stagnalis in vitro (PubMed:10964941).SUBUNIT Interacts with EGFR and promotes EGFR dimerization. Interacts with RHBDF2 (By similarity). Interacts with RHBDF1; may retain EGF in the endoplasmic reticulum and regulates its degradation through the endoplasmic reticulum-associated degradation (ERAD).TISSUE SPECIFICITY Expressed in kidney, salivary gland, cerebrum and prostate.PTM O-glycosylated with core 1-like and core 2-like glycans. It is uncertain if Ser-954 or Thr-955 is O-glycosylated. The modification here shows glycan heterogeneity: HexHexNAc (major) and Hex2HexNAc2 (minor). UniProt P01133 971 EQUAL 1023 EQUAL Reactome Database ID Release 82 179860 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=179860 Reactome R-HSA-179860 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-179860.1 Reactome Database ID Release 82 179882 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=179882 Reactome R-HSA-179882 2 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-179882.2 Reactome DB_ID: 9018569 1 EGF:p-6Y-EGFR dimer:NICD3 [plasma membrane] EGF:p-6Y-EGFR dimer:NICD3 Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 179882 1 Reactome Database ID Release 82 9018569 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=9018569 Reactome R-HSA-9018569 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-9018569.1 Reactome Database ID Release 82 9018573 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=9018573 Reactome R-HSA-9018573 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-9018573.1 25125655 Pubmed 2014 EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling Arasada, Rajeswara Rao Amann, Joseph M Rahman, Mohammad A Huppert, Stacey S Carbone, David P Cancer Res. 74:5572-84 2.7.10.2 EGFR phosphorylates NOTCH3 EGFR phosphorylates NOTCH3 EGFR phosphorylates intracellular domain of NOTCH3 (NICD3) on an unknown tyrosine residue. EGFR signaling inhibits NICD3-mediated transcription. It is not known whether EGFR-mediated phosphorylation of NICD3 affects NICD3 nuclear translocation or the formation of the NOTCH3 coactivator complex. Erlotinib treatment, which inhibits EGFR activation, results in increased NOTCH3 signaling and induction of stem-like phenotype in treated cells (Arasada et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 9018569 1 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 9018581 1 O4'-phospho-L-tyrosine at unknown position 1662 EQUAL 2321 EQUAL Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 179882 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9018569 GO 0004713 GO molecular function Reactome Database ID Release 82 9018582 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=9018582 Reactome Database ID Release 82 9018572 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=9018572 Reactome R-HSA-9018572 2 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-9018572.2 NOTCH3 binds WWP2 NOTCH3 binds WWP2 WWP2, an E3 ubiquitin ligase, can interact with NOTCH3 cleavage products NEXT3 and NICD3 in the cytosol. The interaction involves the PPPY motif in the PEST domain of NOTCH3 (Jung et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 6807279 1 UniProt:O00308 WWP2 WWP2 WWP2 FUNCTION E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.ACTIVITY REGULATION Activated by NDFIP1- and NDFIP2-binding.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with POU5F1, RBP1, EGR2 and SLC11A2 (By similarity). Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts with ERBB4, NDFIP1 AND NDFIP2. Interacts with ARRDC4 (PubMed:23236378). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1 (PubMed:22315426, PubMed:21191027). Interacts (via WW domains) with ARRDC2 and ARRDC3 (PubMed:21191027).SUBUNIT (Microbial infection) Interacts with adenovirus type 2 PIII.TISSUE SPECIFICITY Detected in heart, throughout the brain, placenta, lung, liver, muscle, kidney and pancreas. Also detected in spleen and peripheral blood leukocytes.DEVELOPMENTAL STAGE Highly expressed in undifferentiated embryonic stem cells and expression is reduced after embryoid body (EB) formation. Not detectable at day 13 of EB formation; low levels are again detected at day 18 of EB formation.DOMAIN The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.DOMAIN The WW domains mediate interaction with PPxY motif-containing proteins.PTM Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome.MISCELLANEOUS A cysteine residue is required for ubiquitin-thioester formation. UniProt O00308 1 EQUAL 870 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9021530 1 NEXT3,NICD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NICD3 [cytosol] NEXT3 [plasma membrane] Reactome DB_ID: 9021521 1 NEXT3,NICD3:WWP2 [cytosol] NEXT3,NICD3:WWP2 Reactome DB_ID: 6807279 1 1 EQUAL 870 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9021530 1 Reactome Database ID Release 82 9021521 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=9021521 Reactome R-HSA-9021521 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-9021521.1 Reactome Database ID Release 82 9021520 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=9021520 Reactome R-HSA-9021520 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-9021520.1 25356737 Pubmed 2014 Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer Jung, Jin-Gyoung Stoeck, Alexander Guan, Bin Wu, Ren-Chin Zhu, Heng Blackshaw, S Shih, Ie-Ming Wang, Tian-Li PLoS Genet. 10:e1004751 WWP2 ubiquitinates NOTCH3 WWP2 ubiquitinates NOTCH3 WWP2, an E3 ubiquitin ligase, ubiquitinates NOTCH3 cleavage fragments NEXT3 and NICD3 in the cytosol, targeting them for lysosome-mediated degradation. WWP2 thus negatively regulates NOTCH3 signaling. WWP2 is a putative tumor suppressor whose deletions have been reported in the majority of ovarian carcinomas (Jung et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 9021521 1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 9021524 1 Ub-NEXT3,Ub-NICD3:WWP2 [cytosol] Ub-NEXT3,Ub-NICD3:WWP2 Reactome DB_ID: 6807279 1 1 EQUAL 870 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9021526 1 Ub-NEXT3,Ub-NICD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ub-NEXT3 [plasma membrane] Ub-NICD3 [cytosol] Reactome Database ID Release 82 9021524 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=9021524 Reactome R-HSA-9021524 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-9021524.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9021521 GO 0061630 GO molecular function Reactome Database ID Release 82 9021532 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=9021532 Reactome Database ID Release 82 9021523 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=9021523 Reactome R-HSA-9021523 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-9021523.1 NICD3 traffics to the nucleus NICD3 traffics to the nucleus Based on an analogy with Drosophila Notch and its intracellular cleavage product NICD, it is believed that the cytosolic NICD3 translocates to the nucleus (Lecourtois and Schweisguth 1998, Struhl and Adachi 1998). Authored: Jassal, B, 2005-01-10 12:51:46 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 Reactome DB_ID: 157647 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 157928 1 nucleoplasm GO 0005654 1662 EQUAL 2321 EQUAL Reactome Database ID Release 82 157937 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=157937 Reactome R-HSA-157937 4 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-157937.4 9604939 Pubmed 1998 Nuclear access and action of notch in vivo Struhl, G Adachi, A Cell 93:649-60 9651681 Pubmed 1998 Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos Lecourtois, M Schweisguth, F Curr Biol 8:771-4 Reactome Database ID Release 82 9013507 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=9013507 Reactome R-HSA-9013507 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-9013507.1 10958687 Pubmed 2000 Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2 Shimizu, K Chiba, S Hosoya, N Kumano, K Saito, T Kurokawa, M Kanda, Y Hamada, Y Hirai, H Mol Cell Biol 20:6913-22