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Database: UniProt
Entry: P97677
LinkDB: P97677
Original site: P97677 
ID   DLL1_RAT                Reviewed;         714 AA.
AC   P97677;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1997, sequence version 1.
DT   13-FEB-2019, entry version 150.
DE   RecName: Full=Delta-like protein 1;
DE   AltName: Full=Drosophila Delta homolog 1;
DE            Short=Delta1;
DE   Flags: Precursor;
GN   Name=Dll1;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
OC   Muroidea; Muridae; Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Disibio G., Hebshi L., Boulter J., Weinmaster G.;
RL   Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   GLYCOSYLATION.
RX   PubMed=12036964; DOI=10.1074/jbc.M204445200;
RA   Panin V.M., Shao L., Lei L., Moloney D.J., Irvine K.D.,
RA   Haltiwanger R.S.;
RT   "Notch ligands are substrates for protein O-fucosyltransferase-1 and
RT   Fringe.";
RL   J. Biol. Chem. 277:29945-29952(2002).
RN   [3]
RP   FUNCTION, AND INTERACTION WITH EPN1.
RX   PubMed=22658936; DOI=10.1016/j.devcel.2012.04.005;
RA   Meloty-Kapella L., Shergill B., Kuon J., Botvinick E., Weinmaster G.;
RT   "Notch ligand endocytosis generates mechanical pulling force dependent
RT   on dynamin, epsins, and actin.";
RL   Dev. Cell 22:1299-1312(2012).
RN   [4]
RP   INTERACTION WITH NOTCH1.
RX   PubMed=28089369; DOI=10.1016/j.devcel.2016.12.013;
RA   Kakuda S., Haltiwanger R.S.;
RT   "Deciphering the fringe-mediated notch code: identification of
RT   activating and inhibiting sites allowing discrimination between
RT   ligands.";
RL   Dev. Cell 40:193-201(2017).
CC   -!- FUNCTION: Transmembrane ligand protein of NOTCH1, NOTCH2 and
CC       NOTCH3 receptors that binds the extracellular domain (ECD) of
CC       Notch receptor in a cis and trans fashion manner (By similarity).
CC       Following transinteraction, ligand cells produce mechanical force
CC       that depends of a clathrin-mediated endocytosis, requiring ligand
CC       ubiquitination, EPN1 interaction, and actin polymerisation; these
CC       events promote Notch receptor extracellular domain (NECD)
CC       transendocytosis and triggers Notch signaling through induction of
CC       cleavage, hyperphosphorylation, and nuclear accumulation of the
CC       intracellular domain of Notch receptors (NICD) (PubMed:22658936).
CC       Is required for embryonic development and maintenance of adult
CC       stem cells in many different tissues and immune systeme; the DLL1-
CC       induced Notch signaling is mediated through an intercellular
CC       communication that regulates cell lineage, cell specification,
CC       cell patterning and morphogenesis through effects on
CC       differentiation and proliferation (By similarity). Plays a role in
CC       brain development at different level, namely by regulating
CC       neuronal differentiation of neural precursor cells via cell-cell
CC       interaction, most likely through the lateral inhibitory system in
CC       an endogenous level dependent-manner. During neocortex
CC       development, Dll1-Notch signaling transmission is mediated by
CC       dynamic interactions between intermediate neurogenic progenitors
CC       and radial glia; the cell-cell interactions are mediated via
CC       dynamic and transient elongation processes, likely to
CC       reactivate/maintain Notch activity in neighboring progenitors, and
CC       coordinate progenitor cell division and differentiation across
CC       radial and zonal boundaries. During cerebellar development,
CC       regulates Bergmann glial monolayer formation and its morphological
CC       maturation through a Notch signaling pathway. At the retina and
CC       spinal cord level, regulates neurogenesis by preventing the
CC       premature differentiation of neural progenitors and also by
CC       maintaining progenitors in spinal cord through Notch signaling
CC       pathway. Also controls neurogenesis of the neural tube in a
CC       progenitor domain-specific fashion along the dorsoventral axis.
CC       Maintains quiescence of neural stem cells and plays a role as a
CC       fate determinant that segregates asymmetrically to one daughter
CC       cell during neural stem cells mitosis, resulting in neuronal
CC       differentiation in Dll1-inheriting cell. Plays a role in immune
CC       systeme development, namely the development of all T-cells and
CC       marginal zone (MZ) B cells (By similarity). Blocks the
CC       differentiation of progenitor cells into the B-cell lineage while
CC       promoting the emergence of a population of cells with the
CC       characteristics of a T-cell/NK-cell precursor (By similarity).
CC       Also plays a role during muscle development. During early
CC       development, inhibits myoblasts differentiation from the medial
CC       dermomyotomal lip and later regulates progenitor cell
CC       differentiation. Directly modulates cell adhesion and basal lamina
CC       formation in satellite cells through Notch signaling. Maintains
CC       myogenic progenitors pool by suppressing differentiation through
CC       down-regulation of MYOD1 and is required for satellite cell homing
CC       and PAX7 expression. During craniofacial and trunk myogenesis
CC       suppresses differentiation of cranial mesoderm-derived and somite-
CC       derived muscle via MYOD1 regulation but in cranial mesoderm-
CC       derived progenitors, is neither required for satellite cell homing
CC       nor for PAX7 expression. Also plays a role during pancreatic cell
CC       development. During type B pancreatic cell development, may be
CC       involved in the initiation of proximodistal patterning in the
CC       early pancreatic epithelium. Stimulates multipotent pancreatic
CC       progenitor cells proliferation and pancreatic growth by
CC       maintaining HES1 expression and PTF1A protein levels. During fetal
CC       stages of development, is required to maintain arterial identity
CC       and the responsiveness of arterial endothelial cells for VEGFA
CC       through regulation of KDR activation and NRP1 expression. Controls
CC       sprouting angiogenesis and subsequent vertical branch formation
CC       througth regulation on tip cell differentiation. Negatively
CC       regulates goblet cell differentiation in intestine and controls
CC       secretory fat commitment through lateral inhibition in small
CC       intestine. Plays a role during inner ear development; negatively
CC       regulates auditory hair cell differentiation. Plays a role during
CC       nephron development through Notch signaling pathway. Regulates
CC       growth, blood pressure and energy homeostasis (By similarity).
CC       {ECO:0000250|UniProtKB:O00548, ECO:0000250|UniProtKB:Q61483,
CC       ECO:0000269|PubMed:22658936}.
CC   -!- SUBUNIT: Homodimer. Interacts with TJP1. Interacts with MAGI1 (via
CC       PDZ domain); forms a complex with CTNNB1 and CDH2 and promotes
CC       recruitment to the adherens junction and stabilization on the cell
CC       surface. Interacts with PSEN1; undergoes a presenilin-dependent
CC       gamma-secretase cleavage that releases a Dll1-intracellular form.
CC       Interacts with MFAP5. Interacts with MIB1. Interacts with NEURL1B;
CC       leads to ubiquitination. Interacts with NEURL1 (By similarity).
CC       Interacts with SYNJ2BP; enhances DLL1 protein stability, and
CC       promotes Notch signaling in endothelial cells. Interacts with
CC       MAGI1, MAGI2, MAGI3 and MPDZ (By similarity). Interacts (via
CC       ubiquitin) with EPN1 (via IUM domain); binding with NOTCH1
CC       attached to neighboring cell, promotes ligand ubiquitination and
CC       EPN1 interaction, leading to NECD transendocytosis and Notch
CC       signaling (PubMed:22658936). Interacts with NOTCH1
CC       (PubMed:28089369). {ECO:0000250|UniProtKB:O00548,
CC       ECO:0000250|UniProtKB:Q61483, ECO:0000269|PubMed:22658936,
CC       ECO:0000269|PubMed:28089369}.
CC   -!- SUBCELLULAR LOCATION: Apical cell membrane
CC       {ECO:0000250|UniProtKB:Q61483}; Single-pass type I membrane
CC       protein {ECO:0000250|UniProtKB:Q61483}. Cell junction, adherens
CC       junction {ECO:0000250|UniProtKB:Q61483}. Membrane raft
CC       {ECO:0000250|UniProtKB:Q61483}. Note=Distributed around adherens
CC       junction in the apical endfeet through interactions with MAGI1.
CC       {ECO:0000250|UniProtKB:Q61483}.
CC   -!- PTM: Ubiquitinated by MIB (MIB1 or MIB2), leading to its
CC       endocytosis and subsequent degradation (By similarity).
CC       Ubiquitinated; promotes recycling back to the plasma membrane and
CC       confers a strong affinity for NOTCH1. Mono- and multi-
CC       ubiquitinated. Multi-ubiquitination of LYS-605 by MIB1 promotes
CC       both cis and trans-interaction with NOTCH1, as well as activation
CC       of Notch signaling. Ubiquitinated by NEURL1B (By similarity).
CC       {ECO:0000250|UniProtKB:P10041, ECO:0000250|UniProtKB:Q61483}.
CC   -!- PTM: Phosphorylated in a membrane association-dependent manner.
CC       Phosphorylation at Ser-688 requires the presence of Ser-685,
CC       whereas phosphorylation at Thr-630 and Ser-685 occur independently
CC       of the other sites. Phosphorylation is required for full ligand
CC       activity in vitro and affects surface presentation, ectodomain
CC       shedding, and endocytosis. {ECO:0000250|UniProtKB:Q61483}.
CC   -!- PTM: O-fucosylated. Can be elongated to a disaccharide by MFNG.
CC       {ECO:0000269|PubMed:12036964}.
DR   EMBL; U78889; AAB37343.1; -; mRNA.
DR   RefSeq; NP_114452.1; NM_032063.2.
DR   UniGene; Rn.10628; -.
DR   ProteinModelPortal; P97677; -.
DR   SMR; P97677; -.
DR   BioGrid; 249876; 3.
DR   IntAct; P97677; 2.
DR   STRING; 10116.ENSRNOP00000019934; -.
DR   iPTMnet; P97677; -.
DR   PhosphoSitePlus; P97677; -.
DR   PaxDb; P97677; -.
DR   PRIDE; P97677; -.
DR   GeneID; 84010; -.
DR   KEGG; rno:84010; -.
DR   UCSC; RGD:70949; rat.
DR   CTD; 28514; -.
DR   RGD; 70949; Dll1.
DR   eggNOG; ENOG410IR7B; Eukaryota.
DR   eggNOG; ENOG410XUNS; LUCA.
DR   HOGENOM; HOG000267024; -.
DR   HOVERGEN; HBG007139; -.
DR   InParanoid; P97677; -.
DR   KO; K06051; -.
DR   OrthoDB; 406049at2759; -.
DR   PhylomeDB; P97677; -.
DR   PRO; PR:P97677; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005912; C:adherens junction; ISS:UniProtKB.
DR   GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0005112; F:Notch binding; IPI:UniProtKB.
DR   GO; GO:0014002; P:astrocyte development; ISS:UniProtKB.
DR   GO; GO:0009912; P:auditory receptor cell fate commitment; NAS:UniProtKB.
DR   GO; GO:0001709; P:cell fate determination; TAS:RGD.
DR   GO; GO:0021688; P:cerebellar molecular layer formation; ISS:UniProtKB.
DR   GO; GO:0021693; P:cerebellar Purkinje cell layer structural organization; ISS:UniProtKB.
DR   GO; GO:0072583; P:clathrin-dependent endocytosis; IDA:UniProtKB.
DR   GO; GO:0097102; P:endothelial tip cell fate specification; ISS:UniProtKB.
DR   GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR   GO; GO:0046331; P:lateral inhibition; ISS:UniProtKB.
DR   GO; GO:0002315; P:marginal zone B cell differentiation; ISS:UniProtKB.
DR   GO; GO:0045596; P:negative regulation of cell differentiation; ISS:UniProtKB.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0045605; P:negative regulation of epidermal cell differentiation; ISS:UniProtKB.
DR   GO; GO:0030857; P:negative regulation of epithelial cell differentiation; ISS:UniProtKB.
DR   GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:UniProtKB.
DR   GO; GO:0045662; P:negative regulation of myoblast differentiation; ISS:UniProtKB.
DR   GO; GO:0045665; P:negative regulation of neuron differentiation; ISS:UniProtKB.
DR   GO; GO:0072006; P:nephron development; ISS:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; NAS:UniProtKB.
DR   GO; GO:0048665; P:neuron fate specification; ISS:UniProtKB.
DR   GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB.
DR   GO; GO:0007219; P:Notch signaling pathway; ISS:UniProtKB.
DR   GO; GO:0060853; P:Notch signaling pathway involved in arterial endothelial cell fate commitment; ISS:UniProtKB.
DR   GO; GO:0035265; P:organ growth; ISS:UniProtKB.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0045807; P:positive regulation of endocytosis; ISS:UniProtKB.
DR   GO; GO:0045747; P:positive regulation of Notch signaling pathway; IDA:UniProtKB.
DR   GO; GO:0048633; P:positive regulation of skeletal muscle tissue growth; ISS:UniProtKB.
DR   GO; GO:1903672; P:positive regulation of sprouting angiogenesis; ISS:UniProtKB.
DR   GO; GO:0009954; P:proximal/distal pattern formation; ISS:UniProtKB.
DR   GO; GO:0008217; P:regulation of blood pressure; ISS:UniProtKB.
DR   GO; GO:0051302; P:regulation of cell division; ISS:UniProtKB.
DR   GO; GO:0040008; P:regulation of growth; ISS:UniProtKB.
DR   GO; GO:0050767; P:regulation of neurogenesis; ISS:UniProtKB.
DR   GO; GO:0048631; P:regulation of skeletal muscle tissue growth; ISS:UniProtKB.
DR   GO; GO:0014807; P:regulation of somitogenesis; ISS:UniProtKB.
DR   GO; GO:1900746; P:regulation of vascular endothelial growth factor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0060041; P:retina development in camera-type eye; ISS:UniProtKB.
DR   GO; GO:0060042; P:retina morphogenesis in camera-type eye; ISS:UniProtKB.
DR   GO; GO:0048630; P:skeletal muscle tissue growth; ISS:UniProtKB.
DR   GO; GO:0098773; P:skin epidermis development; ISS:UniProtKB.
DR   GO; GO:0001756; P:somitogenesis; ISS:UniProtKB.
DR   GO; GO:0021510; P:spinal cord development; ISS:UniProtKB.
DR   GO; GO:0003323; P:type B pancreatic cell development; ISS:UniProtKB.
DR   InterPro; IPR001774; DSL.
DR   InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR   InterPro; IPR013032; EGF-like_CS.
DR   InterPro; IPR000742; EGF-like_dom.
DR   InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR   InterPro; IPR018097; EGF_Ca-bd_CS.
DR   InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR   InterPro; IPR011651; Notch_ligand_N.
DR   Pfam; PF01414; DSL; 1.
DR   Pfam; PF00008; EGF; 5.
DR   Pfam; PF07645; EGF_CA; 1.
DR   Pfam; PF07657; MNNL; 1.
DR   SMART; SM00051; DSL; 1.
DR   SMART; SM00181; EGF; 8.
DR   SMART; SM00179; EGF_CA; 6.
DR   SUPFAM; SSF57184; SSF57184; 1.
DR   PROSITE; PS00010; ASX_HYDROXYL; 3.
DR   PROSITE; PS51051; DSL; 1.
DR   PROSITE; PS00022; EGF_1; 8.
DR   PROSITE; PS01186; EGF_2; 8.
DR   PROSITE; PS50026; EGF_3; 7.
DR   PROSITE; PS01187; EGF_CA; 2.
PE   1: Evidence at protein level;
KW   Cell junction; Cell membrane; Complete proteome;
KW   Developmental protein; Differentiation; Disulfide bond;
KW   EGF-like domain; Glycoprotein; Isopeptide bond; Membrane;
KW   Notch signaling pathway; Phosphoprotein; Reference proteome; Repeat;
KW   Signal; Transmembrane; Transmembrane helix; Ubl conjugation.
FT   SIGNAL        1     17       {ECO:0000255}.
FT   CHAIN        18    714       Delta-like protein 1.
FT                                /FTId=PRO_0000007508.
FT   TOPO_DOM     18    537       Extracellular. {ECO:0000255}.
FT   TRANSMEM    538    560       Helical. {ECO:0000255}.
FT   TOPO_DOM    561    714       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN      176    220       DSL. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00377}.
FT   DOMAIN      225    253       EGF-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      256    284       EGF-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      291    324       EGF-like 3. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      331    362       EGF-like 4; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      369    401       EGF-like 5. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      408    439       EGF-like 6. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      446    477       EGF-like 7; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      484    515       EGF-like 8. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   REGION      711    714       Interaction with MAGI1.
FT                                {ECO:0000250|UniProtKB:Q61483}.
FT   MOD_RES     630    630       Phosphothreonine.
FT                                {ECO:0000250|UniProtKB:Q61483}.
FT   MOD_RES     685    685       Phosphoserine; by PKB.
FT                                {ECO:0000250|UniProtKB:Q61483}.
FT   MOD_RES     688    688       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:Q61483}.
FT   CARBOHYD    476    476       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID    178    187       {ECO:0000250}.
FT   DISULFID    191    203       {ECO:0000250}.
FT   DISULFID    211    220       {ECO:0000250}.
FT   DISULFID    225    236       {ECO:0000250}.
FT   DISULFID    229    242       {ECO:0000250}.
FT   DISULFID    244    253       {ECO:0000250}.
FT   DISULFID    256    267       {ECO:0000250}.
FT   DISULFID    262    273       {ECO:0000250}.
FT   DISULFID    275    284       {ECO:0000250}.
FT   DISULFID    291    303       {ECO:0000250}.
FT   DISULFID    297    313       {ECO:0000250}.
FT   DISULFID    315    324       {ECO:0000250}.
FT   DISULFID    331    342       {ECO:0000250}.
FT   DISULFID    336    351       {ECO:0000250}.
FT   DISULFID    353    362       {ECO:0000250}.
FT   DISULFID    369    380       {ECO:0000250}.
FT   DISULFID    374    390       {ECO:0000250}.
FT   DISULFID    392    401       {ECO:0000250}.
FT   DISULFID    408    419       {ECO:0000250}.
FT   DISULFID    413    428       {ECO:0000250}.
FT   DISULFID    430    439       {ECO:0000250}.
FT   DISULFID    446    457       {ECO:0000250}.
FT   DISULFID    451    466       {ECO:0000250}.
FT   DISULFID    468    477       {ECO:0000250}.
FT   DISULFID    484    495       {ECO:0000250}.
FT   DISULFID    489    504       {ECO:0000250}.
FT   DISULFID    506    515       {ECO:0000250}.
FT   CROSSLNK    605    605       Glycyl lysine isopeptide (Lys-Gly)
FT                                (interchain with G-Cter in ubiquitin).
FT                                {ECO:0000250|UniProtKB:Q61483}.
SQ   SEQUENCE   714 AA;  77379 MW;  4B8EE2272BAEA27E CRC64;
     MGRRSALALA VVSALLCQVW SSGVFELKLQ EFVNKKGLLG NRNCCRGGSG PPCACRTFFR
     VCLKHYQASV SPEPPCTYGS AVTAVLGVDS FSLPDGAGID PAFSNPIRFP FGFTWPGTFS
     LIIEALHTDS PDDLATENPE RLISRLTTQR HLTVGEEWSQ DLHSSGRTDL RYSYRFVCDE
     HYYGEGCSVF CRPRDDAFGH FTCGERGEKM CDPGWKGQYC TDPICLPGCD DQHGYCDKPG
     ECKCRVGWQG RYCDECIRYP GCLHGTCQQP WQCNCQEGWG GLFCNQDLNY CTHHKPCRNG
     ATCTNTGQGS YTCSCRPGYT GANCELEVDE CAPSPCRNGG SCTDLEDSYS CTCPPGFYGK
     VCELSAMTCA DGPCFNGGRC SDNPDGGYTC HCPAGFSGFN CEKKIDLCSS SPCSNGAKCV
     DLGNSYLCRC QTGFSGRYCE DNVDDCASSP CANGGTCRDS VNDFSCTCPP GYTGRNCSAP
     VSRCEHAPCH NGATCHQRGQ RYMCECAQGY GGANCQFLLP EPPPDLIVAA QGGSFPWVAV
     CAGVVLVLLL LLGCAAVVVC VRLKLQKHQP PPDPCGGETE TMNNLANCQR EKDVSVSIIG
     ATQIKNTNKK ADFHGDHGAD KSSFKARYPT VDYNLIRDLK GDEATVRDAH SKRDTKCQSQ
     GSVGEEKSTS TLRGGEVPDR KRPESVYSTS KDTKYQSVYV LSAEKDECVI ATEV
//
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