BioPAX pathway converted from "NEXT3 is cleaved to produce NICD3" in the Reactome database. 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 plasma membrane GO 0005886 UniProt:Q9UM47 NOTCH3 NOTCH3 NOTCH3 FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination (PubMed:15350543). Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with PSMA1. Interacts with HIF1AN.TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.DOMAIN The EGF-like domains 10 and 11 are required for binding the ligands JAG1 and DLL1.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.PTM Hydroxylated by HIF1AN.SIMILARITY Belongs to the NOTCH family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q9UM47 Chain Coordinates 1629 EQUAL 2321 EQUAL Reactome DB_ID: 157657 1 1629 EQUAL 1661 EQUAL Reactome DB_ID: 157647 1 cytosol GO 0005829 1662 EQUAL 2321 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157343 gamma-secretase complex [plasma membrane] gamma-secretase complex 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 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: 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 APH1A [plasma membrane] APH1B [plasma membrane] UniProt Q96BI3 UniProt Q8WW43 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 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