BioPAX pathway converted from "NOTCH1 PEST domain mutants bind DLL1 " in the Reactome database. LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind DLL1 NOTCH1 PEST domain mutants are expected to bind to DLL1 ligand in an identical fashion to wild-type NOTCH1 (Jarriault et al. 1998, Yang et al. 2005, Cordle et al. 2008). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 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 NOTCH1 PEST domain mutants Reactome DB_ID: 2220939 NOTCH1 P2514Rfs*4 Reactome DB_ID: 2768978 NOTCH1 P2514Rfs*4 Transmembrane Fragment NOTCH1 Pro2514Argfs*4 Transmembrane Fragment NOTCH1 PEST domain mutant P2514Rfs*4 transmembrane fragment Reactome DB_ID: 2768982 UniProt:P46531 NOTCH1 NOTCH1 TAN1 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. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1 (PubMed:11101851, PubMed:12370315). The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ (PubMed:10713164). The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (PubMed:17573339). Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts (via NICD) with MDM2A. Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transcractivation activity. Interacts with THBS4 (By similarity). Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (PubMed:12050162). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (By similarity). Interacts with ZMIZ1. Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain). Interacts with DLL1 and JAG1 (By similarity). Interacts (via NICD domain) with PRAG1 (By similarity). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30598546). Interacts with ZFP64 (By similarity).TISSUE SPECIFICITY In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.DOMAIN Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.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). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).PTM Phosphorylated.PTM O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).PTM Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).PTM Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).SIMILARITY Belongs to the NOTCH family. UniProt P46531 2514 EQUAL L-arginine residue MOD MOD:00011 2515 EQUAL L-valine residue MOD MOD:00029 2516 EQUAL L-proline residue MOD MOD:00024 1665 EQUAL 2516 EQUAL Reactome Database ID Release 81 2768982 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=2768982 Reactome R-HSA-2768982 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-2768982.1 COSMIC COSV53024776 additional information MI MI:0361 COSMIC COSM33946 1 NOTCH1 Extracellular fragment (NECD1) 19xFucT-16xGlcS-2xFucS-NOTCH1(19-1664) Reactome DB_ID: 1983670 extracellular region GENE ONTOLOGY GO:0005576 73 EQUAL O-fucosyl-L-threonine MOD MOD:00813 116 EQUAL 194 EQUAL 232 EQUAL 311 EQUAL 349 EQUAL 466 EQUAL 617 EQUAL 692 EQUAL 767 EQUAL 805 EQUAL 883 EQUAL O-fucosyl-L-serine MOD MOD:00812 921 EQUAL 997 EQUAL 1035 EQUAL 1159 EQUAL 1197 EQUAL 1243 EQUAL 1321 EQUAL 1362 EQUAL 1402 EQUAL 65 EQUAL O-glucosyl-L-serine MOD MOD:00804 146 EQUAL 378 EQUAL 458 EQUAL 496 EQUAL 534 EQUAL 609 EQUAL 647 EQUAL 722 EQUAL 759 EQUAL 797 EQUAL 951 EQUAL 1027 EQUAL 1065 EQUAL 1189 EQUAL 1273 EQUAL 19 EQUAL 1664 EQUAL Reactome Database ID Release 81 1983670 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=1983670 Reactome R-HSA-1983670 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-1983670.1 1 Reactome Database ID Release 81 2768978 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=2768978 Reactome R-HSA-2768978 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-2768978.1 NOTCH1 Q2395* NOTCH1 Gln2395* Reactome DB_ID: 2902190 NOTCH1 Q2395* Transmembrane Fragment NOTCH1 Gln2395* Transmembrane Fragment Reactome DB_ID: 1485596 2395 EQUAL L-glutamine removal MOD MOD:01637 1665 EQUAL 2394 EQUAL Reactome Database ID Release 81 1485596 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=1485596 Reactome R-HSA-1485596 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-1485596.1 COSMIC COSV53056886 1 1 Reactome Database ID Release 81 2902190 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=2902190 Reactome R-HSA-2902190 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-2902190.1 NOTCH1 Q2440* NOTCH1 Gln2440* Reactome DB_ID: 2902189 NOTCH1 Q2440* Transmembrane Fragment NOTCH1 Gln2440* Transmembrane Fragment Reactome DB_ID: 1485602 2440 EQUAL 1665 EQUAL 2439 EQUAL Reactome Database ID Release 81 1485602 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=1485602 Reactome R-HSA-1485602 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-1485602.1 COSMIC COSV53024887 1 1 Reactome Database ID Release 81 2902189 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=2902189 Reactome R-HSA-2902189 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-2902189.1 NOTCH1 P2474Afs*4 Reactome DB_ID: 2902198 NOTCH1 P2474Afs*4 Transmembrane Fragment Reactome DB_ID: 2894873 2474 EQUAL L-alanine residue MOD MOD:00010 2475 EQUAL L-histidine residue MOD MOD:00018 2476 EQUAL 1665 EQUAL 2476 EQUAL Reactome Database ID Release 81 2894873 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=2894873 Reactome R-HSA-2894873 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-2894873.1 COSMIC COSV53084788 1 1 Reactome Database ID Release 81 2902198 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=2902198 Reactome R-HSA-2902198 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-2902198.1 Reactome Database ID Release 81 2220939 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=2220939 Reactome R-HSA-2220939 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-2220939.1 DLL1:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2768988 1 1 Reactome Database ID Release 81 2768988 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=2768988 Reactome R-HSA-2768988 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-2768988.1 Reactome Database ID Release 81 2769008 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=2769008 Reactome R-HSA-2769008 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-2769008.2 15574878 Pubmed 2005 Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1 Yang, LT Nichols, JT Yao, C Manilay, JO Robey, EA Weinmaster, G Mol Biol Cell 16:927-42 9819428 Pubmed 1998 Delta-1 activation of notch-1 signaling results in HES-1 transactivation Jarriault, S Le, Bail O Hirsinger, E Pourquie, O Logeat, F Strong, CF Brou, C Seidah, NG Isra, l A Mol Cell Biol 18:7423-31 18296446 Pubmed 2008 Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity Cordle, J Redfield, C Stacey, M van der Merwe, PA Willis, AC Champion, BR Hambleton, S Handford, Penny A J Biol Chem 283:11785-93