| IED ID | IndEnz0002015393 |
| Enzyme Type ID | protease015393 |
| Protein Name |
Delta-like protein 1 Drosophila Delta homolog 1 Delta1 Cleaved into: Dll1-soluble form Dll1-EC Shed form ; Dll1-derived cell-associated form Dll1-TMIC Membrane-associated fragment ; Dll1-intracellular form Dll1-IC |
| Gene Name | Dll1 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MGRRSALALAVVSALLCQVWSSGVFELKLQEFVNKKGLLGNRNCCRGGSGPPCACRTFFRVCLKHYQASVSPEPPCTYGSAVTPVLGVDSFSLPDGAGIDPAFSNPIRFPFGFTWPGTFSLIIEALHTDSPDDLATENPERLISRLTTQRHLTVGEEWSQDLHSSGRTDLRYSYRFVCDEHYYGEGCSVFCRPRDDAFGHFTCGDRGEKMCDPGWKGQYCTDPICLPGCDDQHGYCDKPGECKCRVGWQGRYCDECIRYPGCLHGTCQQPWQCNCQEGWGGLFCNQDLNYCTHHKPCRNGATCTNTGQGSYTCSCRPGYTGANCELEVDECAPSPCKNGASCTDLEDSFSCTCPPGFYGKVCELSAMTCADGPCFNGGRCSDNPDGGYTCHCPLGFSGFNCEKKMDLCGSSPCSNGAKCVDLGNSYLCRCQAGFSGRYCEDNVDDCASSPCANGGTCRDSVNDFSCTCPPGYTGKNCSAPVSRCEHAPCHNGATCHQRGQRYMCECAQGYGGPNCQFLLPEPPPGPMVVDLSERHMESQGGPFPWVAVCAGVVLVLLLLLGCAAVVVCVRLKLQKHQPPPEPCGGETETMNNLANCQREKDVSVSIIGATQIKNTNKKADFHGDHGAEKSSFKVRYPTVDYNLVRDLKGDEATVRDTHSKRDTKCQSQSSAGEEKIAPTLRGGEIPDRKRPESVYSTSKDTKYQSVYVLSAEKDECVIATEV |
| Enzyme Length | 722 |
| Uniprot Accession Number | Q61483 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | 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:21985982, PubMed:10958687). 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) (PubMed:10958687, PubMed:18676613). 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:17194759, PubMed:19562077, PubMed:18997111, PubMed:23695674, PubMed:16495313, PubMed:21238454, PubMed:22282195, PubMed:7671806, PubMed:17960184, PubMed:22529374, PubMed:19389377, PubMed:23699523, PubMed:19144989, PubMed:23688253, PubMed:23806616, PubMed:26114479, PubMed:22940113, PubMed:25220152, PubMed:20081190, PubMed:21572390, PubMed:22096075). 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 (PubMed:7671806, PubMed:18997111). 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 (PubMed:23699523). During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway (PubMed:23688253). 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 (PubMed:19389377, PubMed:26114479). Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis (PubMed:20081190). 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 (PubMed:23695674). Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B cells (PubMed:15146182, PubMed:19217325). 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 (By similarity). Upon MMP14 cleavage, negatively regulates Notch signaling in haematopoietic progenitor cells to specifically maintain normal B-cell development in bone marrow (PubMed:21572390). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation (PubMed:17194759). 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 (PubMed:22940113). 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 (PubMed:25220152). 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 (PubMed:22529374). Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels (PubMed:22096075). 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 (PubMed:19144989). Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation (PubMed:22282195). Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine (PubMed:21238454, PubMed:21915337). Plays a role during inner ear development; negatively regulates auditory hair cell differentiation (PubMed:16495313). Plays a role during nephron development through Notch signaling pathway (PubMed:23806616). Regulates growth, blood pressure and energy homeostasis (PubMed:19562077). {ECO:0000250|UniProtKB:O00548, ECO:0000250|UniProtKB:P97677, ECO:0000269|PubMed:10958687, ECO:0000269|PubMed:15146182, ECO:0000269|PubMed:16495313, ECO:0000269|PubMed:17194759, ECO:0000269|PubMed:17960184, ECO:0000269|PubMed:18676613, ECO:0000269|PubMed:18997111, ECO:0000269|PubMed:19144989, ECO:0000269|PubMed:19217325, ECO:0000269|PubMed:19389377, ECO:0000269|PubMed:19562077, ECO:0000269|PubMed:20081190, ECO:0000269|PubMed:21238454, ECO:0000269|PubMed:21572390, ECO:0000269|PubMed:21915337, ECO:0000269|PubMed:21985982, ECO:0000269|PubMed:22096075, ECO:0000269|PubMed:22282195, ECO:0000269|PubMed:22529374, ECO:0000269|PubMed:22940113, ECO:0000269|PubMed:23688253, ECO:0000269|PubMed:23695674, ECO:0000269|PubMed:23699523, ECO:0000269|PubMed:23806616, ECO:0000269|PubMed:25220152, ECO:0000269|PubMed:26114479, ECO:0000269|PubMed:7671806}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Chain (4); Compositional bias (1); Cross-link (1); Disulfide bond (27); Domain (9); Glycosylation (1); Modified residue (3); Mutagenesis (8); Region (2); Sequence conflict (1); Signal peptide (1); Site (2); Topological domain (2); Transmembrane (1) |
| Keywords | Cell junction;Cell membrane;Developmental protein;Differentiation;Direct protein sequencing;Disulfide bond;EGF-like domain;Glycoprotein;Isopeptide bond;Membrane;Notch signaling pathway;Nucleus;Phosphoprotein;Reference proteome;Repeat;Signal;Transmembrane;Transmembrane helix;Ubl conjugation |
| Interact With | Q9WVQ1 |
| Induction | INDUCTION: Induced by PTF1A in multipotent pancreatic progenitor cells (PubMed:22096075). Induced by CDX1 and CDX2 during somitogenesis and goblet cell differentiation (PubMed:22015720). {ECO:0000269|PubMed:22015720, ECO:0000269|PubMed:22096075}. |
| Subcellular Location | SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000269|PubMed:24715457}; Single-pass type I membrane protein {ECO:0000269|PubMed:24715457}. Cell junction, adherens junction {ECO:0000269|PubMed:15908431, ECO:0000269|PubMed:24715457}. Membrane raft {ECO:0000269|PubMed:18676613, ECO:0000269|PubMed:21985982}. Note=Distributed around adherens junction in the apical endfeet through interactions with MAGI1. {ECO:0000269|PubMed:15908431, ECO:0000269|PubMed:24715457}.; SUBCELLULAR LOCATION: [Dll1-derived cell-associated form]: Cell membrane {ECO:0000269|PubMed:12794186}.; SUBCELLULAR LOCATION: [Dll1-intracellular form]: Nucleus {ECO:0000269|PubMed:12794186}. |
| Modified Residue | MOD_RES 638; /note=Phosphothreonine; /evidence=ECO:0000269|PubMed:24449764; MOD_RES 693; /note=Phosphoserine; by PKB; /evidence=ECO:0000269|PubMed:24449764; MOD_RES 696; /note=Phosphoserine; /evidence=ECO:0000269|PubMed:24449764 |
| Post Translational Modification | PTM: Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation. Ubiquitinated; promotes recycling back to the plasma membrane and confers a strong affinity for NOTCH1 (PubMed:18676613). Multi-ubiquitination of LYS-613 by MIB1 promotes both cis and trans-interaction with NOTCH1, as well as activation of Notch signaling (PubMed:21985982). Ubiquitinated by NEURL1B (PubMed:17003037). {ECO:0000250|UniProtKB:P10041, ECO:0000269|PubMed:17003037, ECO:0000269|PubMed:18676613, ECO:0000269|PubMed:21985982}.; PTM: Phosphorylated in a membrane association-dependent manner. Phosphorylation at Ser-696 requires the presence of Ser-693, whereas phosphorylation at Thr-638 and Ser-693 occurs independently of the other sites. Phosphorylation is required for full ligand activity in vitro and affects surface presentation, ectodomain shedding, and endocytosis. {ECO:0000269|PubMed:24449764}.; PTM: Cleaved by MMP14; negatively regulates DLL1-induced Notch signaling in HPCs, modulating B-lymphocyte differentiation in bone marrow (PubMed:21572390). Undergoes two consecutive processing events: a shedding event, partially by ADAM10, that generates a soluble extracellular form and an intracellular membrane-anchored form, followed by a gamma-secretase cleavage releasing an intracellular fragment (PubMed:12794186). {ECO:0000269|PubMed:12794186, ECO:0000269|PubMed:21572390}.; PTM: O-fucosylated. Can be elongated to a disaccharide by MFNG. {ECO:0000250|UniProtKB:P97677}. |
| Signal Peptide | SIGNAL 1..17; /evidence=ECO:0000255 |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 10021340; 10079256; 10080181; 10196361; 10330372; 10393122; 10473134; 10473135; 10476967; 10498685; 10557208; 10615124; 10631167; 10675782; 10704388; 10804169; 10821758; 10837027; 10842072; 10878608; 10879540; 10906448; 10932180; 10952889; 11002339; 11017084; 11035934; 11044610; 11044625; 11060244; 11076679; 11118901; 11124811; 11133162; 11171333; 11262239; 11562355; 11567612; 11578869; 11581320; 11713346; 11731257; 11739954; 11747084; 11807030; 11823422; 11900971; 11912004; 11934853; 11937492; 11973278; 12001066; 12036964; 12167404; 12175503; 12194867; 12217323; 12354787; 12397111; 12421720; 12441287; 12551931; 12588854; 12588999; 12617809; 12620991; 12636920; 12670869; 12697902; 12730123; 12730124; 12839624; 12846471; 12866128; 12900443; 12925591; 12971992; 14517990; 14529612; 14651921; 14660750; 14681479; 14701881; 14732396; 14745966; 14757642; 14960495; 15084498; 15107403; 15133515; 15155583; 15198674; 15242798; 15257302; 15314075; 15459106; 15465493; 15465494; 15469977; 15485825; 15486060; 15494433; 15496443; 15499562; 15509766; 15537664; 15545629; 15574878; 15634781; 15649475; 15689374; 15728481; 15800025; 15821257; 15845899; 15857914; 15866159; 15902259; 15927725; 15930111; 15937931; 15976074; 15979417; 15986483; 16000382; 16061358; 16075367; 16095582; 16109169; 16127714; 16141072; 16141228; 16245338; 16291790; 16324690; 16342160; 16368932; 16393955; 16410412; 16412699; 16452096; 16467359; 16469766; 16508312; 16518823; 16602821; 16621992; 16715081; 16728475; 16728479; 16766699; 16914494; 16943278; 17015435; 17074316; 17107962; 17116431; 17141158; 17150988; 17179084; 17196193; 17210915; 17229764; 17234965; 17251195; 17257418; 17273555; 17306789; 17319963; 17325035; 17336907; 17360776; 17476283; 17477400; 17537796; 17572911; 17582329; 17584735; 17605079; 17625108; 17664336; 17666427; 17670789; 17681139; 17685488; 17823936; 17880938; 17898542; 17928865; 17937396; 17947672; 17986227; 18039969; 18045842; 18093989; 18094025; 18157121; 18164701; 18209061; 18213589; 18234727; 18245833; 18257070; 18270576; 18299190; 18346943; 18371447; 18381350; 18400163; 18495817; 18505817; 18547789; 18590718; 18591437; 18688026; 18694942; 18703040; 18708576; 18725516; 18786568; 18794329; 18824585; 18832397; 18956012; 18957511; 19050235; 19074312; 19103755; 19110448; 19118645; 19130928; 19161597; 19164599; 19168680; 19181931; 19191219; 19208224; 19223466; 19298012; 19369401; 19383720; 19501082; 19501159; 19502490; 19521566; 19549527; 19686682; 19701191; 19723505; 19853565; 19897741; 19906845; 19914171; 20017954; 20231851; 20335360; 20346937; 20412781; 20417196; 20510365; 20548034; 20558143; 20558326; 20561433; 20602435; 20610746; 20727173; 20805985; 20810995; 20883684; 21074523; 21074524; 21098559; 21124801; 21147753; 21235539; 21252157; 21256124; 21267068; 21311046; 21346194; 21368122; 21478884; 21559415; 21677750; 21750033; 21750544; 21752535; 21752929; 21791528; 21829655; 21880902; 21931765; 21949024; 21963425; 22031906; 22069191; 22072963; 22081605; 22249198; 22258620; 22323600; 22390640; 22430492; 22432025; 22445366; 22464328; 22484060; 22554696; 22624713; 22675208; 22675211; 22771497; 22819676; 22944320; 23000963; 23072809; 23111325; 23132245; 23160044; 23223237; 23284862; 23362346; 23362348; 23362349; 23369715; 23437001; 23499991; 23665443; 23671110; 23988615; 23988616; 23988635; 24015274; 24025447; 24073291; 24148613; 24167636; 24227653; 24337118; 24391519; 24443808; 24453338; 24552588; 24647000; 24673559; 24711412; 24801048; 24859004; 24929016; 24943093; 24952961; 24971735; 24982181; 25015359; 25100656; 25378482; 25468943; 25501905; 25535917; 25641698; 25691540; 25703143; 25715394; 25715395; 25725069; 25813538; 25919081; 26387541; 26450967; 26453796; 26514267; 26522918; 26651607; 26728556; 26801181; 26811377; 26911688; 26912775; 26947267; 26988119; 27005988; 27188577; 27510977; 27576369; 27578777; 27631609; 27659682; 27707753; 27719760; 27894818; 28089369; 28319044; 28334989; 28402857; 28537242; 28656980; 28699891; 28714968; 28718206; 28863329; 29031500; 29038036; 29038527; 29140246; 29352015; 29445148; 29712641; 29773667; 29853617; 29961574; 30093553; 30168730; 30181175; 30189017; 30201687; 30289388; 30292786; 30538222; 30590051; 30692224; 30699346; 30796970; 30872278; 30894800; 30940183; 31071093; 31112136; 31171666; 31202705; 31278348; 31504280; 31590629; 31631837; 31676552; 31789450; 31899345; 31934853; 31988190; 32023464; 32029480; 32059775; 32060138; 32094111; 32161758; 32499648; 32719388; 32747435; 32820046; 32855167; 33053343; 33637744; 33795231; 33798452; 33892704; 34035167; 34407390; 34519339; 34583743; 34698766; 3581995; 7490078; 8923452; 9102301; 9109488; 9153393; 9187150; 9207795; 9242490; 9272948; 9291577; 9315901; 9490412; 9539122; 9539123; 9662403; 9690472; 9690473; 9716576; 9739106; 9858718; 9858728; 9876181; 9882480; |
| Motif | |
| Gene Encoded By | |
| Mass | 78,449 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |