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 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NOTCH3 binds DLL4 NOTCH3 binds DLL4 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9981112 1 plasma membrane GO 0005886 UniProt:D3ZHH1 Dll4 Reactome http://www.reactome.org Rattus norvegicus NCBI Taxonomy 10116 UniProt D3ZHH1 Chain Coordinates 27 EQUAL 685 EQUAL Reactome DB_ID: 9980722 1 NOTCH3 [plasma membrane] NOTCH3 Reactome DB_ID: 9980718 1 UniProt:Q9R172 Notch3 UniProt Q9R172 1572 EQUAL 2321 EQUAL Reactome DB_ID: 9980720 1 extracellular region GO 0005576 O-fucosyl-L-threonine at 173 (in Homo sapiens) 173 EQUAL O-fucosyl-L-threonine O-fucosyl-L-threonine at 211 (in Homo sapiens) 211 EQUAL O-fucosyl-L-threonine at 250 (in Homo sapiens) 250 EQUAL O-fucosyl-L-threonine at 290 (in Homo sapiens) 290 EQUAL O-fucosyl-L-threonine at 328 (in Homo sapiens) 328 EQUAL O-fucosyl-L-threonine at 445 (in Homo sapiens) 445 EQUAL O-fucosyl-L-serine at 671 (in Homo sapiens) 671 EQUAL O-fucosyl-L-serine O-fucosyl-L-threonine at 748 (in Homo sapiens) 748 EQUAL O-fucosyl-L-serine at 863 (in Homo sapiens) 863 EQUAL O-fucosyl-L-threonine at 938 (in Homo sapiens) 938 EQUAL O-fucosyl-L-threonine at 1098 (in Homo sapiens) 1098 EQUAL O-fucosyl-L-serine at 1136 (in Homo sapiens) 1136 EQUAL O-fucosyl-L-threonine at 1181 (in Homo sapiens) 1181 EQUAL O-fucosyl-L-serine at 1349 (in Homo sapiens) 1349 EQUAL O-glucosyl-L-serine at 84 (in Homo sapiens) 84 EQUAL O-glucosyl-L-serine O-glucosyl-L-serine at 125 (in Homo sapiens) 125 EQUAL O-glucosyl-L-serine at 357 (in Homo sapiens) 357 EQUAL O-glucosyl-L-serine at 437 (in Homo sapiens) 437 EQUAL O-glucosyl-L-serine at 475 (in Homo sapiens) 475 EQUAL O-glucosyl-L-serine at 513 (in Homo sapiens) 513 EQUAL O-glucosyl-L-serine at 588 (in Homo sapiens) 588 EQUAL O-glucosyl-L-serine at 626 (in Homo sapiens) 626 EQUAL O-glucosyl-L-serine at 663 (in Homo sapiens) 663 EQUAL O-glucosyl-L-serine at 740 (in Homo sapiens) 740 EQUAL O-glucosyl-L-serine at 893 (in Homo sapiens) 893 EQUAL O-glucosyl-L-serine at 968 (in Homo sapiens) 968 EQUAL O-glucosyl-L-serine at 1128 (in Homo sapiens) 1128 EQUAL O-glucosyl-L-serine at 1252 (in Homo sapiens) 1252 EQUAL 40 EQUAL 1571 EQUAL Reactome Database ID Release 82 9980722 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=9980722 Reactome R-RNO-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-RNO-157048.1 Reactome DB_ID: 9986283 1 DLL4:NOTCH3 [plasma membrane] DLL4:NOTCH3 Reactome DB_ID: 9981112 1 27 EQUAL 685 EQUAL Reactome DB_ID: 9980722 1 Reactome Database ID Release 82 9986283 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=9986283 Reactome R-RNO-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-RNO-2168132.1 Reactome Database ID Release 82 9986285 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=9986285 Reactome R-RNO-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-RNO-2168136.1 GO 0007219 GO biological process 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). 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 inferred by electronic annotation IEA GO IEA NOTCH3-ligand complex is cleaved to produce NEXT3 NOTCH3-ligand complex is cleaved to produce NEXT3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10028015 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 Reactome DB_ID: 10028017 1 1629 EQUAL 2321 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10028029 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10028031 ADAM10:Zn2+ [plasma membrane] ADAM10:Zn2+ Reactome DB_ID: 109265 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 9994158 1 UniProt:Q10743 UniProt Q10743 214 EQUAL 748 EQUAL Reactome Database ID Release 82 10028031 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=10028031 Reactome R-RNO-157186 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-RNO-157186.1 GO 0008237 GO molecular function Reactome Database ID Release 82 10028032 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=10028032 Reactome Database ID Release 82 10028034 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=10028034 Reactome R-RNO-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-RNO-9013284.1 GO 0035333 GO biological process 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. 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 inferred by electronic annotation IEA GO IEA 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 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10028017 1 1629 EQUAL 2321 EQUAL Reactome DB_ID: 10028036 1 cytosol GO 0005829 1662 EQUAL 2321 EQUAL Reactome DB_ID: 10028038 1 1629 EQUAL 1661 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9946639 gamma-secretase complex [plasma membrane] gamma-secretase complex Converted from EntitySet in Reactome Reactome DB_ID: 9946637 1 Presenilin [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: 9946626 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 Q0PY50 UniProt A0A0G2K6H8 Reactome DB_ID: 9946629 1 UniProt:Q8CGU6 Ncstn Ncstn Ncstn 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). 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. 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 PEN2. Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Interacts with PSEN1 and PSEN2.PTM N-glycosylated.SIMILARITY Belongs to the nicastrin family. UniProt Q8CGU6 34 EQUAL 709 EQUAL Reactome DB_ID: 2065884 1 UniProt:Q6QI68 Psenen Psenen Psenen 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). 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. PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity.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.SIMILARITY Belongs to the PEN-2 family.CAUTION 3D-structure analysis of the human homolog indicates that the membrane topology differs from the predictions. Contrary to predictions, the N-terminus contains two short helices that dip into the membrane, but do not cross it. The C-terminus contains the single transmembrane helix. This gives rise to a topology where the N-terminus is cytoplasmic and the C-terminus is lumenal. UniProt Q6QI68 1 EQUAL 101 EQUAL Reactome Database ID Release 82 9946639 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=9946639 Reactome R-RNO-157343 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-RNO-157343.1 GO 0004190 GO molecular function Reactome Database ID Release 82 10028039 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=10028039 Reactome Database ID Release 82 10028041 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=10028041 Reactome R-RNO-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-RNO-9013361.1 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). inferred by electronic annotation IEA GO IEA Noncanonical activation of NOTCH3 Noncanonical activation of NOTCH3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NOTCH3 binds YBX1 NOTCH3 binds YBX1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10028260 1 UniProt:P62961 Ybx1 UniProt P62961 2 EQUAL 324 EQUAL Reactome DB_ID: 9980722 1 Reactome DB_ID: 10028262 1 YBX1:NOTCH3 [plasma membrane] YBX1:NOTCH3 Reactome DB_ID: 10028260 1 2 EQUAL 324 EQUAL Reactome DB_ID: 9980722 1 Reactome Database ID Release 82 10028262 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=10028262 Reactome R-RNO-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-RNO-9017807.1 Reactome Database ID Release 82 10028264 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=10028264 Reactome R-RNO-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-RNO-9017797.1 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). 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 inferred by electronic annotation IEA GO IEA 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 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10028262 1 Reactome DB_ID: 10028036 1 1662 EQUAL 2321 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9946639 Reactome Database ID Release 82 10028266 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=10028266 Reactome R-RNO-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-RNO-9017817.1 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). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10037342 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=10037342 Reactome R-RNO-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-RNO-9017802.1 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). inferred by electronic annotation IEA GO IEA NOTCH3 binds activated EGFR NOTCH3 binds activated EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10018979 1 EGF:p-6Y-EGFR dimer [plasma membrane] EGF:p-6Y-EGFR dimer Reactome DB_ID: 9973847 2 EGF:p-6Y-EGFR [plasma membrane] EGF:p-6Y-EGFR Reactome DB_ID: 9944624 1 UniProt:G3V6K6 UniProt G3V6K6 O4'-phospho-L-tyrosine at 992 (in Homo sapiens) 992 EQUAL O4'-phospho-L-tyrosine [MOD:00048] O4'-phospho-L-tyrosine at 1045 (in Homo sapiens) 1045 EQUAL O4'-phospho-L-tyrosine at 1068 (in Homo sapiens) 1068 EQUAL O4'-phospho-L-tyrosine at 1086 (in Homo sapiens) 1086 EQUAL O4'-phospho-L-tyrosine at 1148 (in Homo sapiens) 1148 EQUAL O4'-phospho-L-tyrosine at 1173 (in Homo sapiens) 1173 EQUAL 25 EQUAL 1210 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9944550 1 Homologues of EGF [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Egf [extracellular region] EGF [extracellular region] UniProt P07522 UniProt A0A0G2K5M0 Reactome Database ID Release 82 9973847 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=9973847 Reactome R-RNO-1248702 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-RNO-1248702.1 Reactome Database ID Release 82 10018979 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=10018979 Reactome R-RNO-179882 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-RNO-179882.1 Reactome DB_ID: 10028036 1 1662 EQUAL 2321 EQUAL Reactome DB_ID: 10028280 1 EGF:p-6Y-EGFR dimer:NICD3 [plasma membrane] EGF:p-6Y-EGFR dimer:NICD3 Reactome DB_ID: 10018979 1 Reactome DB_ID: 10028036 1 1662 EQUAL 2321 EQUAL Reactome Database ID Release 82 10028280 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=10028280 Reactome R-RNO-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-RNO-9018569.1 Reactome Database ID Release 82 10028288 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=10028288 Reactome R-RNO-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-RNO-9018573.1 GO 0045746 GO biological process 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). 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 inferred by electronic annotation IEA GO IEA 2.7.10.2 EGFR phosphorylates NOTCH3 EGFR phosphorylates NOTCH3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 10028280 1 Reactome DB_ID: 10018979 1 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10028283 1 O4'-phospho-L-tyrosine at unknown position 1662 EQUAL 2321 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10028280 GO 0004713 GO molecular function Reactome Database ID Release 82 10028284 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=10028284 Reactome Database ID Release 82 10028286 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=10028286 Reactome R-RNO-9018572 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-RNO-9018572.1 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). inferred by electronic annotation IEA GO IEA NOTCH3 binds WWP2 NOTCH3 binds WWP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10028017 1 1629 EQUAL 2321 EQUAL Reactome DB_ID: 10014438 1 UniProt:F7EYF1 UniProt F7EYF1 1 EQUAL 870 EQUAL Reactome DB_ID: 10028716 1 NEXT3,NICD3:WWP2 [cytosol] NEXT3,NICD3:WWP2 Reactome DB_ID: 10028017 1 1629 EQUAL 2321 EQUAL Reactome DB_ID: 10014438 1 1 EQUAL 870 EQUAL Reactome Database ID Release 82 10028716 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=10028716 Reactome R-RNO-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-RNO-9021521.1 Reactome Database ID Release 82 10028718 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=10028718 Reactome R-RNO-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-RNO-9021520.1 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). 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 inferred by electronic annotation IEA GO IEA WWP2 ubiquitinates NOTCH3 WWP2 ubiquitinates NOTCH3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9929766 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rps27a [cytosol] Ubb [cytosol] Ubc [cytosol] Uba52 [cytosol] UniProt P62982 UniProt P0CG51 UniProt Q63429 UniProt P62986 Reactome DB_ID: 10028716 1 Reactome DB_ID: 10028725 1 Ub-NEXT3,Ub-NICD3:WWP2 [cytosol] Ub-NEXT3,Ub-NICD3:WWP2 Reactome DB_ID: 10028721 1 ubiquitinylated lysine (Ub [cytosol]) at unknown position ubiquitinylated lysine [MOD:01148] 1629 EQUAL 2321 EQUAL Reactome DB_ID: 10014438 1 1 EQUAL 870 EQUAL Reactome Database ID Release 82 10028725 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=10028725 Reactome R-RNO-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-RNO-9021524.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10028716 GO 0061630 GO molecular function Reactome Database ID Release 82 10028726 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=10028726 Reactome Database ID Release 82 10028728 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=10028728 Reactome R-RNO-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-RNO-9021523.1 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). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10036612 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=10036612 Reactome R-RNO-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-RNO-9013507.1 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). 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 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 inferred by electronic annotation IEA GO IEA