BioPAX pathway converted from "Signaling by NOTCH2" in the Reactome database. Signaling by NOTCH2 NOTCH2 is activated by binding Delta-like and Jagged ligands (DLL/JAG) expressed in trans on neighboring cells (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). In trans ligand-receptor binding is followed by ADAM10 mediated (Gibb et al. 2010, Shimizu et al. 2000) and gamma secretase complex mediated cleavage of NOTCH2 (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 traffics to the nucleus where it acts as a transcriptional regulator. For a recent review of the cannonical NOTCH signaling, please refer to Kopan and Ilagan 2009, D'Souza et al. 2010, Kovall and Blacklow 2010. CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003) and MDK (midkine) (Huang et al. 2008, Gungor et al. 2011), which plays an important role in epithelial-to-mesenchymal transition, can also bind NOTCH2 and activate NOTCH2 signaling.<br><br>In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). The NICD2:RBPJ:MAML complex activates transcription from RBPJ binding promoter elements (RBEs) (Wu et al. 2000). NOTCH2 coactivator complexes directly stimulate transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets. NOTCH2 but not NOTCH1 coactivator complexes, stimulate FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development (Hubmann et al. 2002). NOTCH2 coactivator complexes together with CREBP1 and EP300 stimulate transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T cells (Maekawa et al. 2008).<br><br>NOTCH2 gene expression is differentially regulated during human B-cell development, with NOTCH2 transcripts appearing at late developmental stages (Bertrand et al. 2000).<br><br> NOTCH2 mutations are a rare cause of Alagille syndrome (AGS). AGS is a dominant congenital multisystem disorder characterized mainly by hepatic bile duct abnormalities. Craniofacial, heart and kidney abnormalities are also frequently observed in the Alagille spectrum (Alagille et al. 1975). AGS is predominantly caused by mutations in JAG1, a NOTCH2 ligand (Oda et al. 1997, Li et al. 1997), but it can also be caused by mutations in NOTCH2 (McDaniell et al. 2006).<br><br><br>Hajdu-Cheney syndrome, an autosomal dominant disorder characterized by severe and progressive bone loss, is caused by NOTCH2 mutations that result in premature C-terminal NOTCH2 truncation, probably leading to increased NOTCH2 signaling (Simpson et al. 2011, Isidor et al. 2011, Majewski et al. 2011). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH2 Activation and Transmission of Signal to the Nucleus Similar to NOTCH1, NOTCH2 is activated by Delta-like and Jagged ligands (DLL/JAG) expressed in trans on a neighboring cell (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). The activation triggers cleavage of NOTCH2, first by ADAM10 at the S2 cleavage site (Gibb et al. 2010, Shimizu et al. 2000), then by gamma-secretase at the S3 cleavage site (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 subsequently traffics to the nucleus where it acts as a transcription regulator. <br><br>While DLL and JAG ligands are well established, canonical NOTCH2 ligands, there is limited evidence that NOTCH2, similar to NOTCH1, can be activated by CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003). MDK (midkine), which plays an important role in epithelial to mesenchymal transition, can also activate NOTCH2 signaling and is able to bind to the extracellular domain of NOTCH2, but the exact mechanism of MDK-induced NOTCH2 activation has not been elucidated (Huang et al. 2008, Gungor et al. 2011). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 LEFT-TO-RIGHT DLL1 binds NOTCH2 DLL1, expressed on the surface of a neighboring cell, binds NOTCH2 and activates NOTCH2-mediated intracellular signaling (Shimizu et al. 2000). Modification of NOTCH2 extracellular domain by fringe enzymes enhances NOTCH2 activation by DLL1 (Hicks et al. 2000). Activation of NOTCH2 signaling by DLL1 may regulate regeneration and proliferation of renal tubules during acute kidney injury (Kobayashi et al. 2008). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Haw, R, 2013-01-14 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 DLL1 Delta 1 ligand Reactome DB_ID: 157089 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:O00548 DLL1 DLL1 UNQ146/PRO172 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. Homo sapiens NCBI Taxonomy 9606 UniProt O00548 18 EQUAL 723 EQUAL Reactome Database ID Release 81 157089 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=157089 Reactome R-HSA-157089 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-157089.1 Reactome http://www.reactome.org Converted from EntitySet in Reactome NOTCH2/Fringe-modified NOTCH2 Reactome DB_ID: 2168114 NOTCH2 NTM-NEC 2 heterodimer Reactome DB_ID: 157005 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) NOTCH2 Extracellular fragment (NECD2) Reactome DB_ID: 1983678 extracellular region GENE ONTOLOGY GO:0005576 UniProt:Q04721 NOTCH2 NOTCH2 FUNCTION Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. 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 (PubMed:21378985, PubMed:21378989). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation (PubMed:29149593). Positively regulates self-renewal of liver cancer cells (PubMed:25985737).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an 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 NOTCH2. Interacts with RELA/p65 (By similarity). Interacts with HIF1AN. Interacts (via ANK repeats) with TCIM, the interaction inhibits the nuclear translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts with CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-protein ligase complex components (PubMed:29149593). Interacts with MINAR1; this interaction increases MINAR1 stability and function (PubMed:29329397). Interacts with NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling pathway in a non-cell-autonomous manner (PubMed:29856954). Interacts with MDK; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519).TISSUE SPECIFICITY Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.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 (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC) (By similarity). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (By similarity). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).PTM Hydroxylated by HIF1AN.PTM Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1.PTM Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the ubiquitin proteasome pathway.SIMILARITY Belongs to the NOTCH family. UniProt Q04721 78 EQUAL O-fucosyl-L-threonine MOD MOD:00813 120 EQUAL 158 EQUAL 197 EQUAL 235 EQUAL 314 EQUAL 352 EQUAL 470 EQUAL 696 EQUAL 771 EQUAL 809 EQUAL 925 EQUAL O-fucosyl-L-serine MOD MOD:00812 963 EQUAL 1001 EQUAL 1039 EQUAL 1077 EQUAL 1163 EQUAL 1201 EQUAL 1318 EQUAL 150 EQUAL O-glucosyl-L-serine MOD MOD:00804 381 EQUAL 462 EQUAL 500 EQUAL 538 EQUAL 613 EQUAL 651 EQUAL 688 EQUAL 726 EQUAL 763 EQUAL 801 EQUAL 879 EQUAL 955 EQUAL 1031 EQUAL 1155 EQUAL 1270 EQUAL 26 EQUAL 1581 EQUAL Reactome Database ID Release 81 1983678 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=1983678 Reactome R-HSA-1983678 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-1983678.1 1 NOTCH2(1582-2471) Notch 2 Transmembrane fragment (NTMIC2) Reactome DB_ID: 157228 1582 EQUAL 2471 EQUAL Reactome Database ID Release 81 157228 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=157228 Reactome R-HSA-157228 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-157228.1 1 Reactome Database ID Release 81 157005 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=157005 Reactome R-HSA-157005 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-157005.1 Sia-Gal-GlcNAc-NOTCH2 Fringe-modified NOTCH2 Reactome DB_ID: 1911528 FRINGE-modified NOTCH2 Extracellular Fragment (NECD2) Reactome DB_ID: 1911518 26 EQUAL 1581 EQUAL Reactome Database ID Release 81 1911518 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=1911518 Reactome R-HSA-1911518 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-1911518.1 1 1 Reactome Database ID Release 81 1911528 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=1911528 Reactome R-HSA-1911528 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-1911528.1 Reactome Database ID Release 81 2168114 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=2168114 Reactome R-HSA-2168114 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-2168114.1 DLL1:NOTCH2 Reactome DB_ID: 1980050 1 1 Reactome Database ID Release 81 1980050 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=1980050 Reactome R-HSA-1980050 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-1980050.1 Reactome Database ID Release 81 1980048 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=1980048 Reactome R-HSA-1980048 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-1980048.1 10934472 Pubmed 2000 Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2 Hicks, C Johnston, SH diSibio, G Collazo, A Vogt, TF Weinmaster, G Nat Cell Biol 2:515-20 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 18418349 Pubmed 2008 Expression and function of the Delta-1/Notch-2/Hes-1 pathway during experimental acute kidney injury Kobayashi, T Terada, Y Kuwana, H Tanaka, H Okado, T Kuwahara, M Tohda, S Sakano, S Sasaki, S Kidney Int 73:1240-50 LEFT-TO-RIGHT JAG1 binds NOTCH2 JAG1, expressed on a neighboring cell, binds NOTCH2 and activates intracellular NOTCH2 signaling (Shimizu et al. 1999, Shimizu et al. 2000). In contrast to NOTCH1, where fringe-mediated modification reduces the affinity of JAG1 for NOTCH1, it seems that fringe-mediated modification of NOTCH2 extracellular domain enhances activation of NOTCH2 signaling by JAG1 (Hicks et al. 2000).<br><br>JAG1-NOTCH2 signaling axis is affected in Alagille syndrome (AGS), a dominant congenital disorder characterized by hepatic bile duct abnormalities, as well as craniofacial, heart and kidney defects (Alagille et al. 1975, Habib et al. 1987). AGS is predominantly caused by mutations in JAG1 (Oda et al. 1997, Li et al. 1997) and less frequently by mutations in NOTCH2 (McDaniell et al. 2006).<br><br>JAG1 and NOTCH2 are expressed in kidney glomeruli and JAG1-NOTH2 signaling plays an important role in kidney development, as shown in mice mutant for JAG1 or NOTCH2 or both (McCright et al. 2001, McCright et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Haw, R, 2013-01-14 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 JAG1 Jagged 1 ligand Reactome DB_ID: 157098 UniProt:P78504 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 Database ID Release 81 157098 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=157098 Reactome R-HSA-157098 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-157098.1 JAG1:NOTCH2 Reactome DB_ID: 1980058 1 1 Reactome Database ID Release 81 1980058 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=1980058 Reactome R-HSA-1980058 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-1980058.1 Reactome Database ID Release 81 1980056 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=1980056 Reactome R-HSA-1980056 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-1980056.1 10551863 Pubmed 1999 Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods Shimizu, K Chiba, S Kumano, K Hosoya, N Takahashi, T Kanda, Y Hamada, Y Yazaki, Y Hirai, H J Biol Chem 274:32961-9 9207787 Pubmed 1997 Mutations in the human Jagged1 gene are responsible for Alagille syndrome Oda, T Elkahloun, A G Pike, B L Okajima, K Krantz, I D Genin, A Piccoli, D A Meltzer, P S Spinner, N B Collins, F S Chandrasekharappa, S C Nat. Genet. 16:235-42 11171333 Pubmed 2001 Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation McCright, B Gao, X Shen, L Lozier, J Lan, Y Maguire, M Herzlinger, D Weinmaster, G Jiang, R Gridley, T Development 128:491-502 16773578 Pubmed 2006 NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway McDaniell, R Warthen, DM Sanchez-Lara, PA Pai, A Krantz, ID Piccoli, DA Spinner, NB Am J Hum Genet 79:169-73 11861489 Pubmed 2002 A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency McCright, Brent Lozier, Julie Gridley, T Development 129:1075-82 803282 Pubmed 1975 Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur Alagille, D Odièvre, Michel Gautier, M Dommergues, J P J. Pediatr. 86:63-71 9207788 Pubmed 1997 Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1 Li, L Krantz, I D Deng, Y Genin, A Banta, A B Collins, C C Qi, M Trask, B J Kuo, W L Cochran, J Costa, T Pierpont, M E Rand, E B Piccoli, D A Hood, L Spinner, N B Nat. Genet. 16:243-51 3153318 Pubmed 1987 Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia) Habib, R Dommergues, J P Gubler, M C Hadchouel, M Gautier, M Odièvre, Michel Alagille, D Pediatr. Nephrol. 1:455-64 LEFT-TO-RIGHT JAG2 binds NOTCH2 JAG2, expressed on a neighboring cell, binds NOTCH2 and activates intracellular NOTCH2 signaling (Shimizu et al. 2000). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Haw, R, 2013-01-14 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 JAG2 Jagged 2 ligand Reactome DB_ID: 157120 UniProt:Q9Y219 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 Database ID Release 81 157120 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=157120 Reactome R-HSA-157120 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-157120.1 JAG2:NOTCH2 Reactome DB_ID: 1980059 1 1 Reactome Database ID Release 81 1980059 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=1980059 Reactome R-HSA-1980059 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-1980059.1 Reactome Database ID Release 81 1980061 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=1980061 Reactome R-HSA-1980061 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-1980061.1 LEFT-TO-RIGHT DLL4 binds NOTCH2 DLL4, expressed on a neighboring cell, binds NOTCH2 receptor and activates NOTCH2 intracellular signaling. The study used recombinant NOTCH2 and DLL4, exogenously expressed in Chinese hamster ovary cells. The species origin of NOTCH2 and DLL4 is not specified in the manuscript by Ji et al. 2004. The impact of fringe-mediated modification of NOTCH2 on activation by DLL4 has not been examined. Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Haw, R, 2013-01-14 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 DLL4 Delta 4 ligand Reactome DB_ID: 158437 UniProt:Q9NR61 DLL4 DLL4 UNQ1895/PRO4341 FUNCTION Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).SUBUNIT Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).TISSUE SPECIFICITY Expressed in vascular endothelium.DOMAIN The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor. UniProt Q9NR61 27 EQUAL 685 EQUAL Reactome Database ID Release 81 158437 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=158437 Reactome R-HSA-158437 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-158437.1 DLL4:NOTCH2 Reactome DB_ID: 1980053 1 1 Reactome Database ID Release 81 1980053 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=1980053 Reactome R-HSA-1980053 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-1980053.1 Reactome Database ID Release 81 1980051 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=1980051 Reactome R-HSA-1980051 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-1980051.1 15569487 Pubmed 2004 Function of Delta4 gene and its effects on 32D cell differentiation Ji, CY Cui, CS Ma, DX Zhao, JQ Guo, NJ Zhang, MH Chin Med J (Engl) 117:1687-92 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of DLL/JAG ligands upon binding to NOTCH2 NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH2 in trans. Integrity of the intracellular domain of DLL1 was shown to be essential for the successful release of NOTCH2 intracellular domain, NICD2, in response to DLL1 binding (Shimizu et al. 2002). In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse Neurl was directly shown to ubiquitinate Jag1 but not other Notch ligands in vitro. N-terminal myristoylation targets Neurl to the plasma membrane and this is a prerequisite for Jag1 internalization (Koutelou et al. 2008). Mouse Neurl1b was shown to directly bind and ubiquitinate recombinant Xenopus Delta and to cooperate with Mib1 in Delta endocytosis (Song et al. 2006). Ubiquitination of NOTCH ligands by MIB and NEURL ubiquitin ligases triggers ligand endocytosis. Drosophila Neuralized needs to interact with membrane phosphoinositides through its phosphoinositide-binding motif to trigger endocytosis of ubiquitinated Delta (Skwarek et al. 2007). The pulling force model states that the endocytosis of ubiquitinated Notch ligands mechanically pulls the ligand-bound Notch receptor, exposing the S2 cleavage site and resulting in Notch receptor cleavage by ADAM10 and/or ADAM17 metalloproteases (Itoh et al. 2003). Using a cell-bead optical tweezers system to measure rupture force specific for cells expressing Dll1 bound to laser trapped Notch1 beads, it was shown that the mechanical force required for the activation of Notch signaling depends on ligand ubiquitination and subsequent clathrin-mediated endocytosis that involves dynamin, epsins and actin (Meloty-Kapella et al. 2012). Ligand endocytosis and recycling does not directly influence Dll1 and Notch1 interaction, except that it regulates the amount of ligand on the cell surface that is available to activate Notch (Shergill et al. 2012). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Haw, R, 2013-01-14 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Edited: Haw, R, 2013-01-14 Converted from EntitySet in Reactome NOTCH2:DSL DLL/JAG:NOTCH2 NOTCH2:DLL/JAG NTM-NEC2-Notch ligand complex Reactome DB_ID: 157637 Reactome Database ID Release 81 157637 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=157637 Reactome R-HSA-157637 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-157637.1 Converted from EntitySet in Reactome Ub ubiquitin Reactome DB_ID: 113595 RPS27A RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939205 cytosol GENE ONTOLOGY GO:0005829 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939205 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=939205 Reactome R-HSA-939205 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-939205.1 UBA52 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939203 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939203 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=939203 Reactome R-HSA-939203 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-939203.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939214 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939214 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=939214 Reactome R-HSA-939214 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-939214.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939213 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939213 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=939213 Reactome R-HSA-939213 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-939213.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939230 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939230 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=939230 Reactome R-HSA-939230 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-939230.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939188 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939188 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=939188 Reactome R-HSA-939188 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-939188.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939164 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939164 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=939164 Reactome R-HSA-939164 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-939164.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939258 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939258 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=939258 Reactome R-HSA-939258 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-939258.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939192 229 EQUAL 304 EQUAL Reactome Database ID Release 81 939192 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=939192 Reactome R-HSA-939192 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-939192.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939232 305 EQUAL 380 EQUAL Reactome Database ID Release 81 939232 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=939232 Reactome R-HSA-939232 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-939232.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939191 381 EQUAL 456 EQUAL Reactome Database ID Release 81 939191 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=939191 Reactome R-HSA-939191 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-939191.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939184 457 EQUAL 532 EQUAL Reactome Database ID Release 81 939184 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=939184 Reactome R-HSA-939184 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-939184.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939239 533 EQUAL 608 EQUAL Reactome Database ID Release 81 939239 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=939239 Reactome R-HSA-939239 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-939239.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939165 609 EQUAL 684 EQUAL Reactome Database ID Release 81 939165 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=939165 Reactome R-HSA-939165 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-939165.1 Reactome Database ID Release 81 113595 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=113595 Reactome R-HSA-113595 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-113595.1 Ub-DLL/JAG:NOTCH2 Reactome DB_ID: 2172171 1 1 Reactome Database ID Release 81 2172171 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=2172171 Reactome R-HSA-2172171 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-2172171.1 ACTIVATION Converted from EntitySet in Reactome MIB/NEURL Mindbomb/Neuralized Reactome DB_ID: 1911464 MIB1 E3 ubiquitin-protein ligase MIB1 Mind bomb homolog 1 Reactome DB_ID: 1472877 UniProt:Q86YT6 MIB1 MIB1 DIP1 KIAA1323 ZZANK2 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF-induced apoptosis (By similarity). Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates 'Lys-63'-linked polyubiquitination of TBK1, which probably participates in kinase activation.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with CEP131 and PCM1.TISSUE SPECIFICITY Widely expressed at low level. Expressed at higher level in spinal cord, ovary, whole brain, and all specific brain regions examined.PTM Ubiquitinated; possibly via autoubiquitination (By similarity). Ubiquitinated; this modification is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock.MISCELLANEOUS In epilepsy brain tissue, levels of expression are increased in the cytoplasm and microsomal fractions (endoplasmic reticulum). UniProt Q86YT6 1 EQUAL 1006 EQUAL Reactome Database ID Release 81 1472877 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=1472877 Reactome R-HSA-1472877 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-1472877.1 MIB2 E3 ubiquitin-protein ligase MIB2 Mind bomb homolog 2 Reactome DB_ID: 1472879 UniProt:Q96AX9 MIB2 MIB2 SKD ZZANK1 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with actin monomer.TISSUE SPECIFICITY Expressed in skeletal muscle, and to a lesser extent in heart, brain and kidney.INDUCTION Down-regulated in many primary skin melanomas. Treatment with a demethylating agent, 5'-aza-2-deoxycytidine, restores expression, suggesting that down-regulation is the result of methylation of the gene.PTM Ubiquitinated. Possibly via autoubiquitination (By similarity). UniProt Q96AX9 1 EQUAL 1013 EQUAL Reactome Database ID Release 81 1472879 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=1472879 Reactome R-HSA-1472879 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-1472879.1 NEURL Neuralized-like protein 1A NEURL1A NEURL1 RNF67 Reactome DB_ID: 1911454 UniProt:O76050 NEURL1 NEURL1 NEURL NEURL1A RNF67 FUNCTION Plays a role in hippocampal-dependent synaptic plasticity, learning and memory. Involved in the formation of spines and functional synaptic contacts by modulating the translational activity of the cytoplasmic polyadenylation element-binding protein CPEB3. Promotes ubiquitination of CPEB3, and hence induces CPEB3-dependent mRNA translation activation of glutamate receptor GRIA1 and GRIA2. Can function as an E3 ubiquitin-protein ligase to activate monoubiquitination of JAG1 (in vitro), thereby regulating the Notch pathway. Acts as a tumor suppressor; inhibits malignant cell transformation of medulloblastoma (MB) cells by inhibiting the Notch signaling pathway.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with CPEB3 (via N-terminal domain); the interaction increases CPEB3 ubiquitination. Interacts with DLL1.TISSUE SPECIFICITY Expressed in brain, testis, pituitary gland, pancreas and bone marrow. Also poorly expressed in malignant astrocytomas and several neuroectodermal tumor cell lines. Weakly expressed in medulloblastoma (MB) compared with normal cerebellar tissues.INDUCTION Down-regulated in medulloblastoma (MB).PTM Myristoylation is a determinant of membrane targeting. UniProt O76050 2 EQUAL 574 EQUAL Reactome Database ID Release 81 1911454 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=1911454 Reactome R-HSA-1911454 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-1911454.1 NEURL1B E3 ubiquitin-protein ligase NEURL1B Neuralized-like protein 1B Neuralized-like protein 3 Reactome DB_ID: 1911456 UniProt:A8MQ27 NEURL1B NEURL1B NEURL3 FUNCTION E3 ubiquitin-protein ligase involved in regulation of the Notch pathway through influencing the stability and activity of several Notch ligands.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with JAG1, DLL1 and DLL4.TISSUE SPECIFICITY Highest expression in brain, prostate and small intestine. In the brain the levels are higher in fetal than in adult stage. In the adult brain the highest levels are detected in the olfactory system, cerebellar cortex, optic nerve and the frontal lobe. UniProt A8MQ27 1 EQUAL 555 EQUAL Reactome Database ID Release 81 1911456 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=1911456 Reactome R-HSA-1911456 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-1911456.1 Reactome Database ID Release 81 1911464 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=1911464 Reactome R-HSA-1911464 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-1911464.1 GENE ONTOLOGY GO:0004842 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 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 81 2172172 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=2172172 Reactome R-HSA-2172172 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-2172172.1 11740940 Pubmed 2001 Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta Lai, EC Deblandre, GA Kintner, C Rubin, GM Dev Cell 1:783-94 22658935 Pubmed 2012 Optical tweezers studies on Notch: single-molecule interaction strength is independent of ligand endocytosis Shergill, Bhupinder Meloty-Kapella, Laurence Musse, Abdiwahab A Weinmaster, G Botvinick, Elliot Dev. Cell 22:1313-20 15760269 Pubmed 2005 Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila Le Borgne, R Remaud, S Hamel, S Schweisguth, F PLoS Biol 3:e96 11823422 Pubmed 2002 Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain Shimizu, K Chiba, S Saito, T Takahashi, T Kumano, K Hamada, Y Hirai, H EMBO J 21:294-302 18077452 Pubmed 2008 Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1 Koutelou, E Sato, S Tomomori-Sato, C Florens, Laurence A Swanson, SK Washburn, MP Kokkinaki, M Conaway, Ron C Conaway, Joan W Moschonas, NK J Biol Chem 283:3846-53 16093323 Pubmed 2005 The interplay between DSL proteins and ubiquitin ligases in Notch signaling Pitsouli, C Delidakis, C Development 132:4041-50 12530964 Pubmed 2003 Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta Itoh, M Kim, CH Palardy, G Oda, T Jiang, YJ Maust, D Yeo, SY Lorick, K Wright, GJ Ariza-McNaughton, L Weissman, AM Lewis, J Chandrasekharappa, SC Chitnis, AB Dev Cell 4:67-82 18043734 Pubmed 2007 An obligatory role of mind bomb-1 in notch signaling of mammalian development Koo, BK Yoon, MJ Yoon, KJ Im, SK Kim, YY Kim, CH Suh, PG Jan, YN Kong, YY PLoS One 2:e1221 22658936 Pubmed 2012 Notch ligand endocytosis generates mechanical pulling force dependent on dynamin, epsins, and actin Meloty-Kapella, Laurence Shergill, Bhupinder Kuon, Jane Botvinick, Elliot Weinmaster, G Dev. Cell 22:1299-312 15829515 Pubmed 2005 The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta Lai, EC Roegiers, F Qin, X Jan, YN Rubin, GM Development 132:2319-32 17003037 Pubmed 2006 Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1 Song, R Koo, BK Yoon, KJ Yoon, MJ Yoo, KW Kim, HT Oh, HJ Kim, YY Han, JK Kim, CH Kong, YY J Biol Chem 281:36391-400 15824097 Pubmed 2005 Mind bomb-2 is an E3 ligase for Notch ligand Koo, BK Yoon, KJ Yoo, KW Lim, HS Song, R So, JH Kim, CH Kong, YY J Biol Chem 280:22335-42 LEFT-TO-RIGHT NOTCH2-ligand complex is cleaved to produce NEXT2 Ligand binding induces a conformational change in NOTCH2, through mechanical pulling of NOTCH triggered by endocytosis of the receptor-attached ligand (Meloty-Kapella et al. 2012). This conformational change exposes the S2 site in the extracellular region of NOTCH2 and results in cleavage of NOTCH2 by ADAM10 metalloprotease (Gibb et al. 2010, Groot et al. 2014), generating the membrane-anchored NOTCH2 fragment NEXT2 (Shimizu et al. 2000). The extracellular NOTCH2 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 NEXT2 NOTCH2(1666-2471) Notch 2 NEXT fragment Reactome DB_ID: 157225 1666 EQUAL 2471 EQUAL Reactome Database ID Release 81 157225 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=157225 Reactome R-HSA-157225 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-157225.1 NOTCH2 fragment:DSL NOTCH2 fragment:DLL/JAG Notch 2 ligand-bound fragment-Notch ligand complex Reactome DB_ID: 157630 1 NOTCH2(1582-1665) Notch 2 ligand-bound fragment Reactome DB_ID: 157652 1582 EQUAL 1665 EQUAL Reactome Database ID Release 81 157652 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=157652 Reactome R-HSA-157652 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-157652.1 1 Converted from EntitySet in Reactome DSL DLL/JAG NOTCH Ligand Reactome DB_ID: 157643 Reactome Database ID Release 81 157643 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=157643 Reactome R-HSA-157643 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-157643.1 1 Reactome Database ID Release 81 157630 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=157630 Reactome R-HSA-157630 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-157630.1 ACTIVATION ADAM10:Zn2+ ADAM 10 metalloprotease (Zn cofactor) Reactome DB_ID: 157186 Zn2+ Zn++ zinc(2+) zinc Zn(II) Reactome DB_ID: 109265 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 81 109265 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=109265 Reactome R-ALL-109265 3 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-ALL-109265.3 COMPOUND C00038 additional information MI MI:0361 1 KUZ ADAM10 ADAM 10 metalloprotease Reactome DB_ID: 157237 UniProt:O14672 ADAM10 ADAM10 KUZ 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 Database ID Release 81 157237 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=157237 Reactome R-HSA-157237 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-157237.1 1 Reactome Database ID Release 81 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 GENE ONTOLOGY GO:0008237 Reactome Database ID Release 81 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 81 157629 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=157629 Reactome R-HSA-157629 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-157629.2 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 20156974 Pubmed 2010 ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo Gibb, DR El Shikh, M Kang, DJ Rowe, WJ El Sayed, R Cichy, J Yagita, H Tew, JG Dempsey, PJ Crawford, HC Conrad, DH J Exp Med 207:623-35 LEFT-TO-RIGHT 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 NEXT2 is cleaved to produce NICD2 NEXT2 fragment of NOTCH2 is further cleaved at the S3 site by the gamma-secretase complex, which releases the intracellular domain NICD2 into the cytosol (Saxena et al. 2001, De Strooper et al. 1999, Schroeter et al. 1998, Fortini 2002). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 TM2 NOTCH2(1666-1696) NOTCH2-TM Transmembrane remnant 2 Reactome DB_ID: 157628 1666 EQUAL 1696 EQUAL Reactome Database ID Release 81 157628 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=157628 Reactome R-HSA-157628 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-157628.1 NICD2 NOTCH2(1697-2471) NICD 2 fragment N2ICD Reactome DB_ID: 157642 1697 EQUAL 2471 EQUAL Reactome Database ID Release 81 157642 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=157642 Reactome R-HSA-157642 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-157642.1 ACTIVATION activeUnit: #Complex13 gamma-secretase complex Reactome DB_ID: 157343 NCSTN Nicastrin NICA_HUMAN Reactome DB_ID: 2534241 UniProt:Q92542 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 Reactome Database ID Release 81 2534241 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=2534241 Reactome R-HSA-2534241 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-2534241.1 1 PEN-2 PSENEN Reactome DB_ID: 157331 UniProt:Q9NZ42 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 Database ID Release 81 157331 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=157331 Reactome R-HSA-157331 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-157331.1 1 Converted from EntitySet in Reactome APH-1 Reactome DB_ID: 157341 APH1B APH-1B Reactome DB_ID: 157340 UniProt:Q8WW43 APH1B APH1B PSFL UNQ688/PRO1328 FUNCTION Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.SUBUNIT Probable component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist (By similarity). Interacts with PSEN1 and PSEN2.TISSUE SPECIFICITY Weakly or not expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, colon, skeletal muscle, heart and brain.SIMILARITY Belongs to the APH-1 family. UniProt Q8WW43 1 EQUAL 257 EQUAL Reactome Database ID Release 81 157340 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=157340 Reactome R-HSA-157340 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-157340.1 APH1A Gamma-secretase subunit APH-1A APH1A_HUMAN Reactome DB_ID: 3211581 UniProt:Q96BI3 APH1A APH1A PSF CGI-78 UNQ579/PRO1141 FUNCTION Non-catalytic 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:12297508, PubMed:12522139, PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, PubMed:19369254). 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).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/PEN2 (PubMed:12297508, PubMed:12740439, PubMed:19369254, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:30598546, PubMed:30630874).TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.SIMILARITY Belongs to the APH-1 family. UniProt Q96BI3 1 EQUAL 265 EQUAL Reactome Database ID Release 81 3211581 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=3211581 Reactome R-HSA-3211581 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-3211581.1 Reactome Database ID Release 81 157341 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=157341 Reactome R-HSA-157341 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-157341.1 1 Converted from EntitySet in Reactome PSEN Presenilin Reactome DB_ID: 9013333 PSEN2 PSEN2 dimer Presenilin-2 Reactome DB_ID: 157352 PSEN2(298-448) PSEN2 C-terminal fragment Presenilin-2 CTF subunit Reactome DB_ID: 9013329 UniProt:P49810 PSEN2 PSEN2 AD4 PS2 PSNL2 STM2 FUNCTION Probable catalytic 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). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369).SUBUNIT Interacts with DOCK3 (By similarity). Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with HERPUD1, FLNA, FLNB and PARL.TISSUE SPECIFICITY Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.DOMAIN The PAL motif is required for normal active site conformation.PTM Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments.PTM Phosphorylated on serine residues.SIMILARITY Belongs to the peptidase A22A family. UniProt P49810 298 EQUAL 448 EQUAL Reactome Database ID Release 81 9013329 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=9013329 Reactome R-HSA-9013329 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-9013329.1 1 PSEN2(1-297) PSEN2 N-terminal fragment Presenilin-2 NTF subunit Reactome DB_ID: 201599 1 EQUAL 297 EQUAL Reactome Database ID Release 81 201599 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=201599 Reactome R-HSA-201599 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-201599.2 1 Reactome Database ID Release 81 157352 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=157352 Reactome R-HSA-157352 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-157352.2 PS1 PSEN1 Presenillin-1 PSEN1 dimer Reactome DB_ID: 2534316 PSEN1(299-467) Presenilin-1 C-terminal fragment Presenilin-1 CTF subunit Reactome DB_ID: 2534245 UniProt:P49768 PSEN1 PSEN1 AD3 PS1 PSNL1 FUNCTION Catalytic 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:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). 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 (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:25394380, PubMed:16959576). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).SUBUNIT Homodimer. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:25394380, PubMed:30598546, PubMed:30630874). Such minimal complex is sufficient for secretase activity (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. As part of the gamma-secretase complex, interacts with CRB2 (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment (PubMed:15274632). Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (via transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation (PubMed:11953314). Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:9738936, PubMed:9437013, PubMed:10551805, PubMed:10037471, PubMed:11953314, PubMed:11799129, PubMed:16126725). Interacts through its N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with DOCK3 (By similarity). Interacts with isoform 1 and isoform 3 of UBQLN1 (PubMed:21143716).TISSUE SPECIFICITY Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level) (PubMed:11987239). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8641442, PubMed:8574969).DOMAIN The PAL motif is required for normal active site conformation.DOMAIN Substrates, such as NOTCH1 and APP peptides, are bound between PSEN1 transmembrane domains and via the first lumenal loop and the cytoplasmic loop between the sixth and seventh transmembrane domains. Substrate binding causes a conformation change and formation of an intermolecular antiparallel beta-sheet between PSEN1 and its substrates.PTM Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.PTM After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.SIMILARITY Belongs to the peptidase A22A family. UniProt P49768 299 EQUAL 467 EQUAL Reactome Database ID Release 81 2534245 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=2534245 Reactome R-HSA-2534245 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-2534245.2 1 PSEN1(1-298) Presenilin-1 N-terminal fragment presenilin-1 NTF subunit Reactome DB_ID: 2534298 1 EQUAL 298 EQUAL Reactome Database ID Release 81 2534298 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=2534298 Reactome R-HSA-2534298 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-2534298.2 1 Reactome Database ID Release 81 2534316 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=2534316 Reactome R-HSA-2534316 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-2534316.2 Reactome Database ID Release 81 9013333 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=9013333 Reactome R-HSA-9013333 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-9013333.1 1 Reactome Database ID Release 81 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 GENE ONTOLOGY GO:0004190 Reactome Database ID Release 81 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 81 157640 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=157640 Reactome R-HSA-157640 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-157640.2 12209127 Pubmed 2002 Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling Fortini, ME Nat Rev Mol Cell Biol 3:673-84 10206645 Pubmed 1999 A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain De Strooper, B Annaert, W Cupers, P Saftig, P Craessaerts, K Mumm, JS Schroeter, EH Schrijvers, V Wolfe, MS Ray, WJ Goate, A Kopan, R Nature 398:518-22 9620803 Pubmed 1998 Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain Schroeter, EH Kisslinger, JA Kopan, R Nature 393:382-6 11518718 Pubmed 2001 Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis Saxena, MT Schroeter, EH Mumm, JS Kopan, R J Biol Chem 276:40268-73 LEFT-TO-RIGHT NICD2 traffics to the nucleus The cytosolic NICD2 translocates to the nucleus. Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 NICD2 NOTCH2(1697-2471) NICD 2 fragment N2ICD Reactome DB_ID: 157942 nucleoplasm GENE ONTOLOGY GO:0005654 1697 EQUAL 2471 EQUAL Reactome Database ID Release 81 157942 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=157942 Reactome R-HSA-157942 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-157942.1 Reactome Database ID Release 81 157933 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=157933 Reactome R-HSA-157933 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-157933.1 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 LEFT-TO-RIGHT NOTCH2 binds CNTN1 CNTN1 (F3, contactin-1) is a neuronal cell adhesion protein that can bind and activate NOTCH2, as well as NOTCH1, and these interactions are thought to play a role in oligodendrocyte maturation. While NOTCH1 activation by CNTN1 was shown to be deltex-dependent, the involvement of deltex in CNTN1-mediated activation of NOTCH2, although likely, has not been examined (Hu et al. 2003). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 CNTN1 Contactin-1/F11/F3 Neural cell surface protein F3 Reactome DB_ID: 373622 UniProt:Q12860 CNTN1 CNTN1 FUNCTION Contactins mediate cell surface interactions during nervous system development. Involved in the formation of paranodal axo-glial junctions in myelinated peripheral nerves and in the signaling between axons and myelinating glial cells via its association with CNTNAP1. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Interaction with TNR induces a repulsion of neurons and an inhibition of neurite outgrowth (By similarity).SUBUNIT Monomer (PubMed:2026173). Interacts with CNTNAP1 in cis form (By similarity). Binds to the carbonic-anhydrase like domain of PTPRZ1 (PubMed:20133774). Interacts with NOTCH1 and TNR. Detected in a complex with NRCAM and PTPRB (By similarity). Interacts with TASOR (By similarity).TISSUE SPECIFICITY Strongly expressed in brain and in neuroblastoma and retinoblastoma cell lines. Lower levels of expression in lung, pancreas, kidney and skeletal muscle.SIMILARITY Belongs to the immunoglobulin superfamily. Contactin family. UniProt Q12860 21 EQUAL 993 EQUAL Reactome Database ID Release 81 373622 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=373622 Reactome R-HSA-373622 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-373622.1 CNTN1:NOTCH2 Reactome DB_ID: 2220817 1 1 Reactome Database ID Release 81 2220817 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=2220817 Reactome R-HSA-2220817 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-2220817.1 Reactome Database ID Release 81 2220816 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=2220816 Reactome R-HSA-2220816 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-2220816.1 14567914 Pubmed 2003 F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation Hu, QD Ang, BT Karsak, M Hu, WP Cui, XY Duka, T Takeda, Y Chia, W Sankar, N Ng, YK Ling, EA Maciag, T Small, D Trifonova, R Kopan, R Okano, H Nakafuku, M Chiba, S Hirai, H Aster, JC Schachner, M Pallen, CJ Watanabe, K Xiao, ZC Cell 115:163-75 LEFT-TO-RIGHT Gamma-secretase cleaves CNTN1:NOTCH2 to release NICD2 Binding of CNTN1 to NOTCH2 results in release of the intracellular domain of NOTCH2, NICD2 in a gamma-secretase-dependent way. The role of ADAM10 metalloprotease in this process has not been directly examined (Hu et al. 2003). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 Reactome Database ID Release 81 2974731 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=2974731 Reactome R-HSA-2974731 3 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-2974731.3 ACTIVATION Reactome Database ID Release 81 2974728 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=2974728 Reactome R-HSA-2974728 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-2974728.1 LEFT-TO-RIGHT NOTCH2 binds MDK MDK (Midkine, MK) is a secreted, heparin-binding growth factor that acts as a homodimer (Iwasaki et al. 1997). Both the full-length and the C-terminal region of MDK can bind the N-terminus of NOTCH2. In the presence of MDK, NICD2 accumulates in the nucleus in a dose-dependent fashion and epithelial-to-mesenchymal-transition (EMT) morphological changes are induced through a mechanism that has not been fully elucidated (Huang et al. 2008, Gungor et al. 2011). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 MDK MDK homodimer Reactome DB_ID: 2974753 MDK Midkine MK1 Reactome DB_ID: 2160953 UniProt:P21741 MDK MDK MK1 NEGF2 FUNCTION Secreted protein that functions as cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors (PubMed:18469519, PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:24458438, PubMed:15466886, PubMed:12084985, PubMed:10772929). Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups (PubMed:12084985, PubMed:10212223). Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration (PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:10683378, PubMed:24458438, PubMed:22323540, PubMed:12084985, PubMed:15466886, PubMed:10772929). Participates in inflammatory processes by exerting two different activities. Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression (PubMed:10683378, PubMed:24458438). This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively (PubMed:10683378). Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation (PubMed:22323540). Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis (By similarity). Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation (By similarity). Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans (By similarity). Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival (PubMed:10212223). Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion (PubMed:12084985, PubMed:1768439). Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2 (PubMed:12084985). Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells (By similarity). Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886, PubMed:1768439). Binds LRP1; promotes neuronal survival (PubMed:10772929). Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation (PubMed:12122009). Promotes epithelial to mesenchymal transition through interaction with NOTCH2 (PubMed:18469519). During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation (By similarity). Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts (By similarity). In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system (By similarity).SUBUNIT Homodimer. Interacts with ALK (PubMed:12122009). Interacts with LRP1; promotes neuronal survival (PubMed:10772929). Interacts with LRP2 (PubMed:10772929). Interacts with NCAM1 (PubMed:10772929). Interacts (via C-terminal) with PTPRZ1 (via chondroitin sulfate chains); this interaction is inhibited by PTN; this interaction promotes neuronal migration (PubMed:10212223). Interacts with NCL; this interaction promotes NCL clustering and lateral movements of this complex into lipid rafts leading to MDK internalization (PubMed:12147681). Interacts with LRP6 and LRP8: this interaction is calcium dependent (PubMed:12573468). Interacts with ITGA4 (PubMed:15466886). Interacts with ITGA6 (PubMed:15466886). Interacts with ITGB1 (PubMed:15466886). Interacts with ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). Interacts with ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886). Interacts with NOTCH2; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519). Interacts with GPC2 (via heparan sulfate chain); this interaction is inhibited by heparin followed by chondroitin sulfate E; this interaction induces GPC2 clustering through heparan sulfate chain; this interaction induces neuronal cell adhesion and neurite outgrowth (PubMed:12084985). Interacts with SDC3; this interaction induces SDC3 clustering; this interaction induces neuronal cell adhesion and neurite outgrowth (PubMed:12084985). Interacts with SDC1 (By similarity). Interacts with CSPG5; this interaction promotes elongation of oligodendroglial precursor-like cells (By similarity).TISSUE SPECIFICITY Expressed in various tumor cell lines. In insulinoma tissue predominantly expressed in precancerous lesions.INDUCTION By heparin and retinoic acid.SIMILARITY Belongs to the pleiotrophin family. UniProt P21741 21 EQUAL 143 EQUAL Reactome Database ID Release 81 2160953 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=2160953 Reactome R-HSA-2160953 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-2160953.1 2 Reactome Database ID Release 81 2974753 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=2974753 Reactome R-HSA-2974753 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-2974753.1 MDK:NOTCH2 Reactome DB_ID: 2974762 1 1 Reactome Database ID Release 81 2974762 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=2974762 Reactome R-HSA-2974762 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-2974762.1 Reactome Database ID Release 81 2974737 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=2974737 Reactome R-HSA-2974737 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-2974737.1 9384573 Pubmed 1997 Solution structure of midkine, a new heparin-binding growth factor Iwasaki, W Nagata, K Hatanaka, H Inui, T Kimura, T Muramatsu, T Yoshida, K Tasumi, M Inagaki, F EMBO J. 16:6936-46 18469519 Pubmed 2008 Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes Huang, Yiping Hoque, Mohammad Obaidul Wu, Feng Trink, Barry Sidransky, David Ratovitski, Edward A Cell Cycle 7:1613-22 21632553 Pubmed 2011 Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer Güngör, Cenap Zander, Hilke Effenberger, Katharina E Vashist, Yogesh K Kalinina, Tatyana Izbicki, Jakob R Yekebas, Emre Bockhorn, Maximilian Cancer Res. 71:5009-19 Reactome Database ID Release 81 2979096 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=2979096 Reactome R-HSA-2979096 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-2979096.1 NOTCH2 intracellular domain regulates transcription In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). NICD2:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (RBEs) (Wu et al. 2000). Besides NICD2, RBPJ and MAML, NOTCH2 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex.<br><br> NOTCH2 coactivator complex directly stimulates transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets.<br><br>The promoter of FCER2 (CD23A) contains several RBEs that are occupied by NOTCH2 but not NOTCH1 coactivator complexes, and NOTCH2 activation stimulates FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBEs, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002).<br><br>NOTCH2 coactivator complex occupies the proximal RBE of the GZMB (granzyme B) promoter and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008). NOTCH2 coactivator complex together with CREBP1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008).<br><br>There are indications that NOTCH2 genetically interacts with hepatocyte nuclear factor 1-beta (HNF1B) in kidney development (Massa et al. 2013, Heliot et al. 2013) and with hepatocyte nuclear factor 6 (HNF6) in bile duct formation (Vanderpool et al. 2012), but the exact nature of these genetic interactions has not been defined.<br><br> Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 LEFT-TO-RIGHT NICD2 binds RBPJ and MAML in the nucleus In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). NICD2:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (Wu et al. 2000). <br> <br>Besides NICD2, RBPJ and MAML, NOTCH2 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD2, it is not shown here. More details are available in the pathway Signaling by NOTCH1.<br><br>Many NOTCH-regulated genes have paired RBPJ-binding sites in their promoters, in head-to-head arrangement, and require cooperative formation of dimeric NOTCH transcription complexes for transcriptional activation (Nam et al. 2007). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 Converted from EntitySet in Reactome MAML Reactome DB_ID: 212357 MAML1 Reactome DB_ID: 212416 UniProt:Q92585 MAML1 MAML1 KIAA0200 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.SUBUNIT Interacts (via N-terminus) with NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (via ankyrin repeat region). Interacts (via N-terminus) with p53 (via DNA-binding region). Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1. Also binds CREBBP/CBP and CDK8.Forms a complex with PRAG1, NOTCH1 and MAML1, in a MAML1-dependent manner (By similarity).TISSUE SPECIFICITY Widely expressed with highest levels in heart, pancreas, peripheral blood leukocytes and spleen.DOMAIN The C-terminal region is required for transcriptional activation.SIMILARITY Belongs to the mastermind family. UniProt Q92585 1 EQUAL 1016 EQUAL Reactome Database ID Release 81 212416 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=212416 Reactome R-HSA-212416 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-212416.1 MAML2 Reactome DB_ID: 212353 UniProt:Q8IZL2 MAML2 MAML2 KIAA1819 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Potentiates activation by NOTCH3 and NOTCH4 more efficiently than MAML1 or MAML3.SUBUNIT Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.TISSUE SPECIFICITY Widely expressed with high levels detected in placenta, salivary gland and skeletal muscle.DOMAIN The C-terminal domain is required for transcriptional activation.DISEASE A chromosomal aberration involving MAML2 is found in mucoepidermoid carcinomas, benign Warthin tumors and clear cell hidradenomas. Translocation t(11;19)(q21;p13) with CRTC1. The fusion protein consists of the N-terminus of CRTC1 joined to the C-terminus of MAML2. The reciprocal fusion protein consisting of the N-terminus of MAML2 joined to the C-terminus of CRTC1 has been detected in a small number of mucoepidermoid carcinomas.SIMILARITY Belongs to the mastermind family. UniProt Q8IZL2 1 EQUAL 1156 EQUAL Reactome Database ID Release 81 212353 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=212353 Reactome R-HSA-212353 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-212353.1 MAML3 MAML3_HUMAN Reactome DB_ID: 349689 UniProt:Q96JK9 MAML3 MAML3 KIAA1816 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1.SUBUNIT Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.DOMAIN The C-terminal domain is required for transcriptional activation.SIMILARITY Belongs to the mastermind family. UniProt Q96JK9 1 EQUAL 1134 EQUAL Reactome Database ID Release 81 349689 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=349689 Reactome R-HSA-349689 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-349689.1 MAMLD1 MAMD1_HUMAN Reactome DB_ID: 349692 UniProt:Q13495 MAMLD1 MAMLD1 CG1 CXorf6 FUNCTION Transactivates the HES3 promoter independently of NOTCH proteins. HES3 is a non-canonical NOTCH target gene which lacks binding sites for RBPJ.TISSUE SPECIFICITY Expressed in fetal brain, fetal ovary and fetal testis. Expressed in adult brain, ovary, skin, testis, uterus. Highly expressed in skeletal muscle.INDUCTION By NR5A1.SIMILARITY Belongs to the mastermind family. UniProt Q13495 1 EQUAL 774 EQUAL Reactome Database ID Release 81 349692 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=349692 Reactome R-HSA-349692 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-349692.1 Reactome Database ID Release 81 212357 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=212357 Reactome R-HSA-212357 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-212357.2 RBPJ Recombining binding protein suppressor of hairless SUH_HUMAN CBF1 Reactome DB_ID: 3008668 UniProt:Q06330 RBPJ RBPJ IGKJRB IGKJRB1 RBPJK RBPSUH FUNCTION Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA (PubMed:21991380). Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen) (PubMed:23303788). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits (By similarity).SUBUNIT Interacts with activated NOTCH1, NOTCH2 or NOTCH3. Interacts with MINT/SHARP. This interaction may mediate the recruitment of large corepressor complexes containing proteins such as HDAC1, HDAC2, NCOR2, SAP30, FHL1/KYOT2 and CIR1. Interacts with EP300, MAML1 and PTF1A. Interacts with Epstein-Barr virus EBNA2, EBNA3, EBNA4 and EBNA6. Interacts with RITA1/C12orf52, leading to nuclear export, prevent the interaction between RBPJ and NICD product and subsequent down-regulation of the Notch signaling pathway. Interacts with SNW1. Interacts with CHCHD2 and CXXC5 (PubMed:23303788). Interacts with BEND6 (via BEN domain). Interacts with NKAPL (By similarity). Interacts with ZMIZ1. Interacts with RBM15 (By similarity).SIMILARITY Belongs to the Su(H) family.CAUTION Despite some similarity with the 'phage' integrase family, it has no recombinase activity. UniProt Q06330 1 EQUAL 500 EQUAL Reactome Database ID Release 81 3008668 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=3008668 Reactome R-HSA-3008668 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-3008668.1 NOTCH2 Coactivator Complex Reactome DB_ID: 2127289 1 1 1 Reactome Database ID Release 81 2127289 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=2127289 Reactome R-HSA-2127289 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-2127289.1 Reactome Database ID Release 81 2197588 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=2197588 Reactome R-HSA-2197588 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-2197588.1 17284587 Pubmed 2007 Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription Nam, Yunsun Sliz, Piotr Pear, Warren S Aster, JC Blacklow, SC Proc. Natl. Acad. Sci. U.S.A. 104:2103-8 11101851 Pubmed 2000 MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors Wu, L Aster, JC Blacklow, SC Lake, R Artavanis-Tsakonas, S Griffin, JD Nat Genet 26:484-9 LEFT-TO-RIGHT NOTCH2 coactivator complex binds HES1 promoter NOTCH2 intracellular domain, NICD2, as a part of the NOTCH2 coactivator complex, binds RBPJ elements in the promoter of HES1 gene (Shimizu et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 HES1 gene Reactome DB_ID: 2197548 ENSEMBL:ENSG00000114315 HES1 HES1 BHLHB39 HL HRY ENSEMBL ENSG00000114315 Reactome Database ID Release 81 2197548 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=2197548 Reactome R-HSA-2197548 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-2197548.2 NOTCH2 Coactivator Complex:HES1 gene Reactome DB_ID: 2976712 1 1 Reactome Database ID Release 81 2976712 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=2976712 Reactome R-HSA-2976712 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-2976712.1 Reactome Database ID Release 81 2976716 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=2976716 Reactome R-HSA-2976716 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-2976716.1 11866432 Pubmed 2002 Functional diversity among Notch1, Notch2, and Notch3 receptors Shimizu, K Chiba, S Saito, T Kumano, K Hamada, Y Hirai, H Biochem Biophys Res Commun 291:775-9 LEFT-TO-RIGHT NOTCH2 stimulates HES1 transcription NOTCH2 coactivator complex bound to RBPJ elements in the promoter of HES1 gene stimulates HES1 transcription (Shimizu et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 HES1 Hairy and enhancer of split 1 Transcription factor HES-1 Reactome DB_ID: 210825 UniProt:Q14469 HES1 HES1 BHLHB39 HL HRY FUNCTION Transcriptional repressor of genes that require a bHLH protein for their transcription. May act as a negative regulator of myogenesis by inhibiting the functions of MYOD1 and ASH1. Binds DNA on N-box motifs: 5'-CACNAG-3' with high affinity and on E-box motifs: 5'-CANNTG-3' with low affinity (By similarity). May play a role in a functional FA core complex response to DNA cross-link damage, being required for the stability and nuclear localization of FA core complex proteins, as well as for FANCD2 monoubiquitination in response to DNA damage.SUBUNIT Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family. Interacts (via WPRW motif) with TLE1, and more weakly with TLE2. Interacts with HES6 (By similarity). Interacts with SIRT1. Interacts with an FA complex, composed of FANCA, FANCF, FANCG and FANCL, but not of FANCC, nor FANCE.DOMAIN Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).DOMAIN The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.DOMAIN The bHLH, as well as cooperation between the central Orange domain and the C-terminal WRPW motif, is required for transcriptional repressor activity. UniProt Q14469 1 EQUAL 280 EQUAL Reactome Database ID Release 81 210825 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=210825 Reactome R-HSA-210825 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-210825.1 Reactome Database ID Release 81 2197562 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=2197562 Reactome R-HSA-2197562 3 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-2197562.3 ACTIVATION activeUnit: #Complex19 Reactome Database ID Release 81 2197555 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=2197555 Reactome R-HSA-2197555 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-2197555.1 LEFT-TO-RIGHT NOTCH2 coactivator complex binds HES5 promoter NOTCH2 intracellular domain, NICD2, as a part of the NOTCH2 coactivator complex, binds RBPJ elements in the promoter of HES5 gene (Shimizu et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 HES5 gene Reactome DB_ID: 2197557 ENSEMBL:ENSG00000197921 HES5 HES5 BHLHB38 ENSEMBL ENSG00000197921 Reactome Database ID Release 81 2197557 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=2197557 Reactome R-HSA-2197557 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-2197557.2 NOTCH2 Coactivator Complex:HES5 gene Reactome DB_ID: 2976724 1 1 Reactome Database ID Release 81 2976724 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=2976724 Reactome R-HSA-2976724 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-2976724.1 Reactome Database ID Release 81 2976726 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=2976726 Reactome R-HSA-2976726 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-2976726.1 LEFT-TO-RIGHT NOTCH2 stimulates transcription of HES5 NOTCH2 coactivator complex bound to HES5 promoter stimulates HES5 transcription (Shimizu et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 HES5 Transcription factor HES-5 Class B basic helix-loop-helix protein 38 Hairy and enhancer of split 5 BHLHB38 Reactome DB_ID: 1606739 UniProt:Q5TA89 HES5 HES5 BHLHB38 FUNCTION Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator (By similarity).SUBUNIT Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.TISSUE SPECIFICITY Expressed in fetal heart and brain tumors.DOMAIN Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).DOMAIN The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins. UniProt Q5TA89 1 EQUAL 166 EQUAL Reactome Database ID Release 81 1606739 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=1606739 Reactome R-HSA-1606739 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-1606739.1 Reactome Database ID Release 81 2197564 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=2197564 Reactome R-HSA-2197564 3 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-2197564.3 ACTIVATION activeUnit: #Complex19 Reactome Database ID Release 81 2197550 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=2197550 Reactome R-HSA-2197550 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-2197550.1 LEFT-TO-RIGHT NOTCH2 coactivator complex binds FCER2 promoter The promoter of FCER2 (CD23A) contains several RBPJ (CSL i.e. CBF) binding sites that are occupied by RBPJ transcription complexes that contain NICD2, but not NICD1. The association of NICD2 with RBPJ promoter elements of FCER2 gene was demonstrated by electromobility shift assays on nuclear extracts of human B-cell chronic lymphocytic leukemia (B-CLL) cells (Hubmann et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 FCER2 gene FCER2 gene on chromosome 19 Reactome DB_ID: 2127282 ENSEMBL:ENSG00000104921 FCER2 FCER2 CD23A CLEC4J FCE2 IGEBF ENSEMBL ENSG00000104921 7753644 EQUAL 7767032 EQUAL Reactome Database ID Release 81 2127282 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=2127282 Reactome R-HSA-2127282 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-2127282.1 NOTCH2 Coactivator Complex:FCER2 gene Reactome DB_ID: 2976740 1 1 Reactome Database ID Release 81 2976740 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=2976740 Reactome R-HSA-2976740 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-2976740.1 Reactome Database ID Release 81 2976742 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=2976742 Reactome R-HSA-2976742 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-2976742.1 11986231 Pubmed 2002 Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia Hubmann, R Schwarzmeier, JD Shehata, M Hilgarth, M Duechler, M Dettke, M Berger, R Blood 99:3742-7 LEFT-TO-RIGHT NOTCH2 stimulates transcription of FCER2 (CD23A) Transient transfection of a human pre-B-cell line REH with a vector encoding recombinant rat NICD2 induces endogenous FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBPJ promoter elements, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 CD23 FCER2(1-321) FCER2 Low affinity immunoglobulin epsilon Fc receptor CD23A Reactome DB_ID: 2127280 UniProt:P06734 FCER2 FCER2 CD23A CLEC4J FCE2 IGEBF FUNCTION Low-affinity receptor for immunoglobulin E (IgE) and CR2/CD21. Has essential roles in the regulation of IgE production and in the differentiation of B-cells (it is a B-cell-specific antigen).SUBUNIT Homotrimer.PTM N- and O-glycosylated.PTM The secreted form sCD23 is produced by ADAM10-mediated ectodomain shedding.MISCELLANEOUS There are two kinds of Fc receptors for IgE, which differ in both structure and function: high affinity receptors on basophils and mast cells and low affinity receptors on lymphocytes and monocytes. UniProt P06734 1 EQUAL 321 EQUAL Reactome Database ID Release 81 2127280 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=2127280 Reactome R-HSA-2127280 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-2127280.1 Reactome Database ID Release 81 2127285 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=2127285 Reactome R-HSA-2127285 3 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-2127285.3 ACTIVATION activeUnit: #Complex19 Reactome Database ID Release 81 2127288 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=2127288 Reactome R-HSA-2127288 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-2127288.1 LEFT-TO-RIGHT NOTCH2 coactivator complex and phosphorylated CREB1 bind GZMB promoter GZMB (granzyme B) promoter contains several RBPJ binding elements (RBEs). NOTCH2 coactivator complex occupies the proximal RBE and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 p300 EP300 Histone acetyltransferase p300 EP300_HUMAN KAT3B Reactome DB_ID: 381325 UniProt:Q09472 EP300 EP300 P300 FUNCTION Functions as histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:8945521). Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Mediates acetylation of histone H3 at 'Lys-27' (H3K27ac) (PubMed:23911289). Also functions as acetyltransferase for non-histone targets, such as ALX1, HDAC1, PRMT1 or SIRT2 (PubMed:12929931, PubMed:16762839, PubMed:18722353). Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of p53/TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Following DNA damage, forms a stress-responsive p53/TP53 coactivator complex with JMY which mediates p53/TP53 acetylation, thereby increasing p53/TP53-dependent transcription and apoptosis (PubMed:11511361, PubMed:15448695). Promotes chromatin acetylation in heat shock responsive HSP genes during the heat shock response (HSR), thereby stimulating HSR transcription (PubMed:18451878). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acetylates 'Lys-247' of EGR2 (By similarity). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates BCL6 wich disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degradation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). Acetylates GABPB1, impairing GABPB1 heterotetramerization and activity (By similarity). Acetylates PCK1 and promotes PCK1 anaplerotic activity (PubMed:30193097). Acetylates RXRA and RXRG (PubMed:17761950). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA), 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), lactoyl-CoA or propanoyl-CoA (propionyl-CoA), and is able to mediate protein crotonylation, butyrylation, 2-hydroxyisobutyrylation, lactylation or propionylation, respectively (PubMed:17267393, PubMed:25818647, PubMed:29775581, PubMed:31645732). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (2E)-butenoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Catalyzes histone lactylation in macrophages by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription (PubMed:31645732). Acts as a protein-lysine 2-hydroxyisobutyryltransferase; regulates glycolysis by mediating 2-hydroxyisobutyrylation of glycolytic enzymes (PubMed:29775581). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein.SUBUNIT Interacts with HIF1A; the interaction is stimulated in response to hypoxia and inhibited by CITED2 (PubMed:9887100, PubMed:11959990). Probably part of a complex with HIF1A and CREBBP (PubMed:8917528). Interacts (via N-terminus) with TFAP2A (via N-terminus); the interaction requires CITED2 (PubMed:12586840). Interacts (via CH1 domain) with CITED2 (via C-terminus) (PubMed:12586840, PubMed:12778114). Interacts with CITED1 (unphosphorylated form preferentially and via C-terminus) (PubMed:10722728, PubMed:16864582). Interacts with ESR1; the interaction is estrogen-dependent and enhanced by CITED1 (PubMed:11581164). Interacts with HIPK2 (By similarity). Interacts with DTX1, EID1, ELF3, FEN1, LEF1, NCOA1, NCOA6, NR3C1, PCAF, PELP1, PRDM6, SP1, SP3, SPIB, SRY, TCF7L2, DDX5, DDX17, SATB1, SRCAP and TRERF1 (PubMed:11073989, PubMed:11073990, PubMed:10823961, PubMed:11349124, PubMed:11430825, PubMed:11481323, PubMed:11564735, PubMed:11581372, PubMed:11864910, PubMed:12446687, PubMed:12527917, PubMed:12837748, PubMed:14605447, PubMed:15075319, PubMed:15297880, PubMed:16478997, PubMed:8684459, PubMed:17226766, PubMed:9590696). Interacts with JMY, the complex activates p53/TP53 transcriptional activity (PubMed:10518217, PubMed:11511361). Interacts with TTC5/STRAP; the interaction facilitates the association between JMY and p300/EP300 cofactors (PubMed:11511361). Interacts with p53/TP53; the interation is facilitated by TTC5/STRAP (PubMed:15186775, PubMed:15448695, PubMed:19217391). Forms a complex with TTC5/STRAP and HSF1; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity (PubMed:18451878). Part of a complex containing CARM1 and NCOA2/GRIP1 (PubMed:11701890, PubMed:11997499, PubMed:15731352). Interacts with ING4 and this interaction may be indirect (PubMed:12750254). Interacts with ING5 (PubMed:12750254). Interacts with the C-terminal region of CITED4 (PubMed:11744733). Non-sumoylated EP300 preferentially interacts with SENP3 (PubMed:19680224). Interacts with SS18L1/CREST (PubMed:14716005). Interacts with ALX1 (via homeobox domain) (PubMed:12929931). Interacts with NEUROD1; the interaction is inhibited by NR0B2 (PubMed:14752053). Interacts with TCF3 (PubMed:14752053). Interacts (via CREB-binding domain) with MYOCD (via C-terminus) (By similarity). Interacts with ROCK2 and PPARG (PubMed:11518699, PubMed:16574662). Forms a complex made of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228). Interacts with IRF1 and this interaction enhances acetylation of p53/TP53 and stimulation of its activity (PubMed:15509808). Interacts with FOXO1; the interaction acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Interacts with ALKBH4 and DDIT3/CHOP (PubMed:17872950, PubMed:23145062). Interacts with KLF15 (PubMed:23999430). Interacts with CEBPB and RORA (PubMed:9862959). Interacts with NPAS2, ARNTL/BMAL1 and CLOCK (PubMed:14645221). Interacts with SIRT2 isoform 1, isoform 2 and isoform 5 (PubMed:24177535). Interacts with MTA1 (PubMed:16617102). Interacts with HDAC4 and HDAC5 in the presence of TFAP2C (PubMed:24413532). Interacts with TRIP4 (PubMed:25219498). Directly interacts with ZBTB49; this interaction leads to synergistic transactivation of CDKN1A (PubMed:25245946). Interacts with NR4A3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with ZBTB48/TZAP (PubMed:24382891). Interacts with STAT1; the interaction is enhanced upon IFN-gamma stimulation (PubMed:26479788). Interacts with HNRNPU (via C-terminus); this interaction enhances DNA-binding of HNRNPU to nuclear scaffold/matrix attachment region (S/MAR) elements (PubMed:11909954). Interacts with BCL11B (PubMed:27959755, PubMed:16809611). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Interacts with NUPR1; this interaction enhances the effect of EP300 on PAX2 transcription factor activity (PubMed:11940591). Interacts with RXRA; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). Interacts with RB1 (By similarity). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295). Interacts with SOX9 (PubMed:12732631). Interacts with ATF4; EP300/p300 stabilizes ATF4 and increases its transcriptional activity independently of its catalytic activity by preventing its ubiquitination (PubMed:16219772). Interacts with KAT5; promoting KAT5 autoacetylation (PubMed:24835996).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction stimulates the acetylation of RB1 by recruiting EP300 and RB1 into a multimeric-protein complex.SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 proteins Tax, p30II and HBZ.DOMAIN The CRD1 domain (cell cycle regulatory domain 1) mediates transcriptional repression of a subset of p300 responsive genes; it can be de-repressed by CDKN1A/p21WAF1 at least at some promoters. It conatins sumoylation and acetylation sites and the same lysine residues may be targeted for the respective modifications. It is proposed that deacetylation by SIRT1 allows sumoylation leading to suppressed activity.PTM Acetylated on Lys at up to 17 positions by intermolecular autocatalysis. Deacetylated in the transcriptional repression domain (CRD1) by SIRT1, preferentially at Lys-1020. Deacetylated by SIRT2, preferentially at Lys-418, Lys-423, Lys-1542, Lys-1546, Lys-1549, Lys-1699, Lys-1704 and Lys-1707.PTM Citrullinated at Arg-2142 by PADI4, which impairs methylation by CARM1 and promotes interaction with NCOA2/GRIP1.PTM Methylated at Arg-580 and Arg-604 in the KIX domain by CARM1, which blocks association with CREB, inhibits CREB signaling and activates apoptotic response. Also methylated at Arg-2142 by CARM1, which impairs interaction with NCOA2/GRIP1.PTM Sumoylated; sumoylation in the transcriptional repression domain (CRD1) mediates transcriptional repression. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.PTM Probable target of ubiquitination by FBXO3, leading to rapid proteasome-dependent degradation.PTM Phosphorylated by HIPK2 in a RUNX1-dependent manner. This phosphorylation that activates EP300 happens when RUNX1 is associated with DNA and CBFB. Phosphorylated by ROCK2 and this enhances its activity. Phosphorylation at Ser-89 by AMPK reduces interaction with nuclear receptors, such as PPARG.DISEASE Defects in EP300 may play a role in epithelial cancer.DISEASE Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. UniProt Q09472 2 EQUAL 2414 EQUAL Reactome Database ID Release 81 381325 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=381325 Reactome R-HSA-381325 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-381325.1 phospho-CREB dimer p-S133-CREB1 homodimer Reactome DB_ID: 111911 CREB p-S133-CREB1 phospho-CREB cAMP response element binding protein Reactome DB_ID: 111910 UniProt:P16220 CREB1 CREB1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family. UniProt P16220 133 EQUAL O-phospho-L-serine MOD MOD:00046 1 EQUAL 341 EQUAL Reactome Database ID Release 81 111910 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=111910 Reactome R-HSA-111910 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-111910.1 2 Reactome Database ID Release 81 111911 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=111911 Reactome R-HSA-111911 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-111911.2 GZMB Gene Reactome DB_ID: 2976052 ENSEMBL:ENSG00000100453 GZMB GZMB CGL1 CSPB CTLA1 GRB ENSEMBL ENSG00000100453 Reactome Database ID Release 81 2976052 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=2976052 Reactome R-HSA-2976052 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-2976052.1 NOTCH2 coactivator complex:p-S133-CREB1:EP300:GZMB Gene Reactome DB_ID: 2976561 1 1 1 1 Reactome Database ID Release 81 2976561 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=2976561 Reactome R-HSA-2976561 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-2976561.2 Reactome Database ID Release 81 2976563 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=2976563 Reactome R-HSA-2976563 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-2976563.2 18724371 Pubmed 2008 Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity Maekawa, Yoichi Minato, Yoshiaki Ishifune, Chieko Kurihara, Takeshi Kitamura, Akiko Kojima, Hidefumi Yagita, H Sakata-Yanagimoto, Mamiko Saito, Toshiki Taniuchi, Ichiro Chiba, Shigeru Sone, Saburo Yasutomo, Koji Nat. Immunol. 9:1140-7 LEFT-TO-RIGHT NOTCH2 stimulates GZMB transcription NOTCH2 coactivator complex together with CREB1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008). Authored: Orlic-Milacic, M, 2013-01-11 Reviewed: Boyle, Scott, 2013-04-25 Reviewed: Ilagan, Ma Xenia, 2013-04-25 Edited: Haw, R, 2013-01-14 HLP GZMB Granzyme B T-cell serine protease 1-3E Cytotoxic T-lymphocyte proteinase 2 Lymphocyte protease SECT Granzyme 2 Cathepsin G-like 1 CTSGL1 CTLA-1 Fragmentin 2 Human lymphocyte protein C11 Reactome DB_ID: 55915 UniProt:P10144 GZMB GZMB CGL1 CSPB CTLA1 GRB FUNCTION Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent pyroptosis when delivered into the target cell through the immunological synapse (PubMed:3262682, PubMed:3263427, PubMed:1985927). It cleaves after Asp (PubMed:8258716, PubMed:1985927). Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-E (GSDME), releasing the pore-forming moiety of GSDME, thereby triggering pyroptosis and target cell death (PubMed:32188940, PubMed:31953257). Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. Cleaves caspase-3, -7, -9 and 10 to give rise to active enzymes mediating apoptosis (PubMed:9852092).ACTIVITY REGULATION Inactivated by the serine protease inhibitor diisopropylfluorophosphate.INDUCTION By staphylococcal enterotoxin A (SEA) in peripheral blood leukocytes.SIMILARITY Belongs to the peptidase S1 family. Granzyme subfamily. UniProt P10144 21 EQUAL 247 EQUAL Reactome Database ID Release 81 55915 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=55915 Reactome R-HSA-55915 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-55915.1 Reactome Database ID Release 81 2976551 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=2976551 Reactome R-HSA-2976551 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-2976551.2 ACTIVATION activeUnit: #Complex19 activeUnit: #Protein55 activeUnit: #Protein56 Reactome Database ID Release 81 2976565 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=2976565 Reactome R-HSA-2976565 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-2976565.1 Reactome Database ID Release 81 2197563 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=2197563 Reactome R-HSA-2197563 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-2197563.1 21898486 Pubmed 2012 Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo Vanderpool, Charles Sparks, Erin E Huppert, Kari A Gannon, Maureen Means, Anna L Huppert, Stacey S Hepatology 55:233-43 23362348 Pubmed 2013 HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2 Heliot, Claire Desgrange, Audrey Buisson, Isabelle Prunskaite-Hyyryläinen, Renata Shan, Jingdong Vainio, Seppo Umbhauer, Muriel Cereghini, Silvia Development 140:873-85 23362349 Pubmed 2013 Hepatocyte nuclear factor 1? controls nephron tubular development Massa, Filippo Garbay, Serge Bouvier, Raymonde Sugitani, Yoshinobu Noda, T Gubler, Marie-Claire Heidet, Laurence Pontoglio, Marco Fischer, Evelyne Development 140:886-96 Reactome Database ID Release 81 1980145 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=1980145 Reactome R-HSA-1980145 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-1980145.2 20816393 Pubmed 2010 Canonical and non-canonical Notch ligands D'Souza, B Meloty-Kapella, L Weinmaster, G Curr Top Dev Biol 92:73-129 19379690 Pubmed 2009 The canonical Notch signaling pathway: unfolding the activation mechanism Kopan, R Ilagan, Ma Xenia Cell 137:216-33 20816392 Pubmed 2010 Mechanistic insights into Notch receptor signaling from structural and biochemical studies Kovall, Rhett A Blacklow, SC Curr. Top. Dev. Biol. 92:31-71 21378989 Pubmed 2011 Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis Isidor, Bertrand Lindenbaum, Pierre Pichon, Olivier Bezieau, Stephane Dina, Christian Jacquemont, Sébastien Martin-Coignard, Dominique Thauvin-Robinet, Christel Le Merrer, M Mandel, Jean-Louis David, Albert Faivre, Laurence Cormier-Daire, Valerie Redon, Richard Le Caignec, Cédric Nat. Genet. 43:306-8 21378985 Pubmed 2011 Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss Simpson, Michael A Irving, Melita D Asilmaz, Esra Gray, Mary J Dafou, Dimitra Elmslie, Frances V Mansour, Sahar Holder, Sue E Brain, Caroline E Burton, Barbara K Kim, Katherine H Pauli, Richard M Aftimos, Salim Stewart, Helen Kim, Chong Ae Holder-Espinasse, Muriel Robertson, Stephen P Drake, William M Trembath, Richard C Nat. Genet. 43:303-5 11187898 Pubmed 2000 Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells Bertrand, FE Eckfeldt, CE Lysholm, AS LeBien, TW Leukemia 14:2095-102 21681853 Pubmed 2011 Mutations in NOTCH2 in families with Hajdu-Cheney syndrome Majewski, Jacek Schwartzentruber, Jeremy A Caqueret, Aurore Patry, Lysanne Marcadier, Janet Fryns, JP Boycott, Kym M Ste-Marie, Louis-Georges McKiernan, Fergus E Marik, Ivo Van Esch, Hilde Hum. Mutat. 32:1114-7 GENE ONTOLOGY GO:0007219 gene ontology term for cellular process MI MI:0359