DLL1_MOUSE
ID DLL1_MOUSE Reviewed; 722 AA.
AC Q61483; Q6PFV7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Delta-like protein 1 {ECO:0000305};
DE AltName: Full=Drosophila Delta homolog 1;
DE Short=Delta1 {ECO:0000303|PubMed:12794186};
DE Contains:
DE RecName: Full=Dll1-soluble form {ECO:0000303|PubMed:12794186};
DE Short=Dll1-EC {ECO:0000305|PubMed:12794186};
DE Short=Shed form {ECO:0000303|PubMed:12794186};
DE Contains:
DE RecName: Full=Dll1-derived cell-associated form {ECO:0000303|PubMed:12794186};
DE Short=Dll1-TMIC {ECO:0000305|PubMed:12794186};
DE Short=Membrane-associated fragment {ECO:0000303|PubMed:12794186};
DE Contains:
DE RecName: Full=Dll1-intracellular form {ECO:0000303|PubMed:12794186};
DE Short=Dll1-IC {ECO:0000305|PubMed:12794186};
DE Flags: Precursor;
GN Name=Dll1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], DEVELOPMENTAL STAGE, TISSUE SPECIFICITY, AND
RP FUNCTION.
RC STRAIN=C57BL/6 X BALB/c; TISSUE=Embryo;
RX PubMed=7671806; DOI=10.1242/dev.121.8.2407;
RA Bettenhausen B., de Angelis M.H., Simon D., Guenet J.-L., Gossler A.;
RT "Transient and restricted expression during mouse embryogenesis of Dll1, a
RT murine gene closely related to Drosophila Delta.";
RL Development 121:2407-2418(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryonic brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PROTEIN SEQUENCE OF 527-534 AND 536-543, PROTEOLYTIC CLEAVAGE BY MMP14,
RP INTERACTION WITH MMP14, IDENTIFICATION BY MASS SPECTROMETRY, AND FUNCTION.
RX PubMed=21572390; DOI=10.1038/emboj.2011.136;
RA Jin G., Zhang F., Chan K.M., Xavier Wong H.L., Liu B., Cheah K.S., Liu X.,
RA Mauch C., Liu D., Zhou Z.;
RT "MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain
RT normal B-cell development.";
RL EMBO J. 30:2281-2293(2011).
RN [6]
RP PROTEIN SEQUENCE OF 536-554, PROTEOLYTIC CLEAVAGE, HOMODIMERIZATION,
RP INTERACTION WITH PSEN1, AND SUBCELLULAR LOCATION.
RX PubMed=12794186; DOI=10.1073/pnas.1230693100;
RA Six E., Ndiaye D., Laabi Y., Brou C., Gupta-Rossi N., Israel A., Logeat F.;
RT "The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and
RT gamma-secretase.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:7638-7643(2003).
RN [7]
RP FUNCTION.
RX PubMed=10958687; DOI=10.1128/mcb.20.18.6913-6922.2000;
RA Shimizu K., Chiba S., Hosoya N., Kumano K., Saito T., Kurokawa M.,
RA Kanda Y., Hamada Y., Hirai H.;
RT "Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces
RT cleavage, nuclear translocation, and hyperphosphorylation of Notch2.";
RL Mol. Cell. Biol. 20:6913-6922(2000).
RN [8]
RP FUNCTION.
RX PubMed=15146182; DOI=10.1038/ni1075;
RA Hozumi K., Negishi N., Suzuki D., Abe N., Sotomaru Y., Tamaoki N.,
RA Mailhos C., Ish-Horowicz D., Habu S., Owen M.J.;
RT "Delta-like 1 is necessary for the generation of marginal zone B cells but
RT not T cells in vivo.";
RL Nat. Immunol. 5:638-644(2004).
RN [9]
RP INTERACTION WITH MFAP5.
RX PubMed=15788413; DOI=10.1074/jbc.m500273200;
RA Nehring L.C., Miyamoto A., Hein P.W., Weinmaster G., Shipley J.M.;
RT "The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces
RT its shedding from the cell surface.";
RL J. Biol. Chem. 280:20349-20355(2005).
RN [10]
RP INTERACTION WITH MAGI1, AND SUBCELLULAR LOCATION.
RX PubMed=15908431; DOI=10.1074/jbc.m500375200;
RA Mizuhara E., Nakatani T., Minaki Y., Sakamoto Y., Ono Y., Takai Y.;
RT "MAGI1 recruits Dll1 to cadherin-based adherens junctions and stabilizes it
RT on the cell surface.";
RL J. Biol. Chem. 280:26499-26507(2005).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=16495313; DOI=10.1242/dev.02284;
RA Brooker R., Hozumi K., Lewis J.;
RT "Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse
RT inner ear.";
RL Development 133:1277-1286(2006).
RN [12]
RP INTERACTION WITH NEURL1B, AND UBIQUITINATION.
RX PubMed=17003037; DOI=10.1074/jbc.m606601200;
RA Song R., Koo B.-K., Yoon K.-J., Yoon M.-J., Yoo K.-W., Kim H.-T., Oh H.-J.,
RA Kim Y.-Y., Han J.-K., Kim C.-H., Kong Y.-Y.;
RT "Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1.";
RL J. Biol. Chem. 281:36391-36400(2006).
RN [13]
RP DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=17194759; DOI=10.1073/pnas.0608281104;
RA Schuster-Gossler K., Cordes R., Gossler A.;
RT "Premature myogenic differentiation and depletion of progenitor cells cause
RT severe muscle hypotrophy in Delta1 mutants.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:537-542(2007).
RN [14]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=18997111; DOI=10.1242/dev.024570;
RA Kawaguchi D., Yoshimatsu T., Hozumi K., Gotoh Y.;
RT "Selection of differentiating cells by different levels of delta-like 1
RT among neural precursor cells in the developing mouse telencephalon.";
RL Development 135:3849-3858(2008).
RN [15]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=17960184; DOI=10.1038/sj.jid.5701113;
RA Estrach S., Cordes R., Hozumi K., Gossler A., Watt F.M.;
RT "Role of the Notch ligand Delta1 in embryonic and adult mouse epidermis.";
RL J. Invest. Dermatol. 128:825-832(2008).
RN [16]
RP UBIQUITINATION, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18676613; DOI=10.1073/pnas.0800695105;
RA Heuss S.F., Ndiaye-Lobry D., Six E.M., Israel A., Logeat F.;
RT "The intracellular region of Notch ligands Dll1 and Dll3 regulates their
RT trafficking and signaling activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:11212-11217(2008).
RN [17]
RP INTERACTION WITH NEURL1 AND NEURL1B.
RX PubMed=19723503; DOI=10.1016/j.bbrc.2009.08.147;
RA Rullinkov G., Tamme R., Sarapuu A., Lauren J., Sepp M., Palm K.,
RA Timmusk T.;
RT "Neuralized-2: Expression in human and rodents and interaction with Delta-
RT like ligands.";
RL Biochem. Biophys. Res. Commun. 389:420-425(2009).
RN [18]
RP DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=19144989; DOI=10.1182/blood-2008-08-174508;
RA Soerensen I., Adams R.H., Gossler A.;
RT "DLL1-mediated Notch activation regulates endothelial identity in mouse
RT fetal arteries.";
RL Blood 113:5680-5688(2009).
RN [19]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=19389377; DOI=10.1016/j.ydbio.2009.01.011;
RA Rocha S.F., Lopes S.S., Gossler A., Henrique D.;
RT "Dll1 and Dll4 function sequentially in the retina and pV2 domain of the
RT spinal cord to regulate neurogenesis and create cell diversity.";
RL Dev. Biol. 328:54-65(2009).
RN [20]
RP FUNCTION.
RX PubMed=19217325; DOI=10.1016/j.immuni.2008.12.016;
RA Tan J.B., Xu K., Cretegny K., Visan I., Yuan J.S., Egan S.E., Guidos C.J.;
RT "Lunatic and manic fringe cooperatively enhance marginal zone B cell
RT precursor competition for delta-like 1 in splenic endothelial niches.";
RL Immunity 30:254-263(2009).
RN [21]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=19562077; DOI=10.1371/journal.pone.0006054;
RA Rubio-Aliaga I., Przemeck G.K., Fuchs H., Gailus-Durner V., Adler T.,
RA Hans W., Horsch M., Rathkolb B., Rozman J., Schrewe A., Wagner S.,
RA Hoelter S.M., Becker L., Klopstock T., Wurst W., Wolf E., Klingenspor M.,
RA Ivandic B.T., Busch D.H., Beckers J., Hrabe de Angelis M.;
RT "Dll1 haploinsufficiency in adult mice leads to a complex phenotype
RT affecting metabolic and immunological processes.";
RL PLoS ONE 4:E6054-E6054(2009).
RN [22]
RP FUNCTION.
RX PubMed=20081190; DOI=10.1242/dev.036806;
RA Marklund U., Hansson E.M., Sundstroem E., de Angelis M.H., Przemeck G.K.,
RA Lendahl U., Muhr J., Ericson J.;
RT "Domain-specific control of neurogenesis achieved through patterned
RT regulation of Notch ligand expression.";
RL Development 137:437-445(2010).
RN [23]
RP MUTAGENESIS OF 613-LYS--LYS-618; LYS-613; LYS-689; LYS-699 AND LYS-713,
RP INTERACTION WITH MIB1, SUBCELLULAR LOCATION, FUNCTION, AND UBIQUITINATION
RP AT LYS-613.
RX PubMed=21985982; DOI=10.1016/j.bbamcr.2011.08.019;
RA Zhang L., Widau R.C., Herring B.P., Gallagher P.J.;
RT "Delta-like 1-Lysine613 regulates notch signaling.";
RL Biochim. Biophys. Acta 1813:2036-2043(2011).
RN [24]
RP FUNCTION.
RX PubMed=21238454; DOI=10.1053/j.gastro.2011.01.005;
RA Pellegrinet L., Rodilla V., Liu Z., Chen S., Koch U., Espinosa L.,
RA Kaestner K.H., Kopan R., Lewis J., Radtke F.;
RT "Dll1- and dll4-mediated notch signaling are required for homeostasis of
RT intestinal stem cells.";
RL Gastroenterology 140:1230-1240(2011).
RN [25]
RP FUNCTION.
RX PubMed=21915337; DOI=10.1371/journal.pone.0024484;
RA Stamataki D., Holder M., Hodgetts C., Jeffery R., Nye E., Spencer-Dene B.,
RA Winton D.J., Lewis J.;
RT "Delta1 expression, cell cycle exit, and commitment to a specific secretory
RT fate coincide within a few hours in the mouse intestinal stem cell
RT system.";
RL PLoS ONE 6:E24484-E24484(2011).
RN [26]
RP FUNCTION.
RX PubMed=22282195; DOI=10.1161/circresaha.111.263319;
RA Napp L.C., Augustynik M., Paesler F., Krishnasamy K., Woiterski J.,
RA Limbourg A., Bauersachs J., Drexler H., Le Noble F., Limbourg F.P.;
RT "Extrinsic Notch ligand Delta-like 1 regulates tip cell selection and
RT vascular branching morphogenesis.";
RL Circ. Res. 110:530-535(2012).
RN [27]
RP FUNCTION, AND INDUCTION.
RX PubMed=22096075; DOI=10.1242/dev.071761;
RA Ahnfelt-Roenne J., Joergensen M.C., Klinck R., Jensen J.N.,
RA Fuechtbauer E.M., Deering T., MacDonald R.J., Wright C.V., Madsen O.D.,
RA Serup P.;
RT "Ptf1a-mediated control of Dll1 reveals an alternative to the lateral
RT inhibition mechanism.";
RL Development 139:33-45(2012).
RN [28]
RP INDUCTION.
RX PubMed=22015720; DOI=10.1016/j.ydbio.2011.09.034;
RA Grainger S., Lam J., Savory J.G., Mears A.J., Rijli F.M., Lohnes D.;
RT "Cdx regulates Dll1 in multiple lineages.";
RL Dev. Biol. 361:1-11(2012).
RN [29]
RP FUNCTION.
RX PubMed=22940113; DOI=10.1016/j.devcel.2012.07.014;
RA Broehl D., Vasyutina E., Czajkowski M.T., Griger J., Rassek C., Rahn H.P.,
RA Purfuerst B., Wende H., Birchmeier C.;
RT "Colonization of the satellite cell niche by skeletal muscle progenitor
RT cells depends on Notch signals.";
RL Dev. Cell 23:469-481(2012).
RN [30]
RP FUNCTION.
RX PubMed=22529374; DOI=10.1073/pnas.1203605109;
RA Horn S., Kobberup S., Joergensen M.C., Kalisz M., Klein T., Kageyama R.,
RA Gegg M., Lickert H., Lindner J., Magnuson M.A., Kong Y.Y., Serup P.,
RA Ahnfelt-Roenne J., Jensen J.N.;
RT "Mind bomb 1 is required for pancreatic beta-cell formation.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:7356-7361(2012).
RN [31]
RP FUNCTION.
RX PubMed=23806616; DOI=10.1016/j.devcel.2013.05.022;
RA Liu Z., Chen S., Boyle S., Zhu Y., Zhang A., Piwnica-Worms D.R.,
RA Ilagan M.X., Kopan R.;
RT "The extracellular domain of Notch2 increases its cell-surface abundance
RT and ligand responsiveness during kidney development.";
RL Dev. Cell 25:585-598(2013).
RN [32]
RP FUNCTION.
RX PubMed=23699523; DOI=10.1523/jneurosci.0791-13.2013;
RA Nelson B.R., Hodge R.D., Bedogni F., Hevner R.F.;
RT "Dynamic interactions between intermediate neurogenic progenitors and
RT radial glia in embryonic mouse neocortex: potential role in Dll1-Notch
RT signaling.";
RL J. Neurosci. 33:9122-9139(2013).
RN [33]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=23688253; DOI=10.1186/1756-6606-6-25;
RA Hiraoka Y., Komine O., Nagaoka M., Bai N., Hozumi K., Tanaka K.;
RT "Delta-like 1 regulates Bergmann glial monolayer formation during
RT cerebellar development.";
RL Mol. Brain 6:25-25(2013).
RN [34]
RP FUNCTION.
RX PubMed=23695674; DOI=10.1038/ncomms2895;
RA Kawaguchi D., Furutachi S., Kawai H., Hozumi K., Gotoh Y.;
RT "Dll1 maintains quiescence of adult neural stem cells and segregates
RT asymmetrically during mitosis.";
RL Nat. Commun. 4:1880-1880(2013).
RN [35]
RP INTERACTION WITH TJP1, AND SUBCELLULAR LOCATION.
RX PubMed=24715457; DOI=10.1242/dev.102988;
RA Hatakeyama J., Wakamatsu Y., Nagafuchi A., Kageyama R., Shigemoto R.,
RA Shimamura K.;
RT "Cadherin-based adhesions in the apical endfoot are required for active
RT Notch signaling to control neurogenesis in vertebrates.";
RL Development 141:1671-1682(2014).
RN [36]
RP FUNCTION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, AND TISSUE
RP SPECIFICITY.
RX PubMed=25220152; DOI=10.1016/j.ydbio.2014.09.005;
RA Czajkowski M.T., Rassek C., Lenhard D.C., Broehl D., Birchmeier C.;
RT "Divergent and conserved roles of Dll1 signaling in development of
RT craniofacial and trunk muscle.";
RL Dev. Biol. 395:307-316(2014).
RN [37]
RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT THR-638; SER-693
RP AND SER-696, AND MUTAGENESIS OF THR-638; SER-693 AND SER-696.
RX PubMed=24449764; DOI=10.1128/mcb.00965-13;
RA Braune E.B., Schuster-Gossler K., Lyszkiewicz M., Serth K., Preusse K.,
RA Madlung J., Macek B., Krueger A., Gossler A.;
RT "S/T phosphorylation of DLL1 is required for full ligand activity in vitro
RT but dispensable for DLL1 function in vivo during embryonic patterning and
RT marginal zone B cell development.";
RL Mol. Cell. Biol. 34:1221-1233(2014).
RN [38]
RP FUNCTION.
RX PubMed=26114479; DOI=10.1371/journal.pgen.1005328;
RA Preusse K., Tveriakhina L., Schuster-Gossler K., Gaspar C., Rosa A.I.,
RA Henrique D., Gossler A., Stauber M.;
RT "Context-dependent functional divergence of the Notch ligands DLL1 and DLL4
RT in vivo.";
RL PLoS Genet. 11:E1005328-E1005328(2015).
CC -!- FUNCTION: Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3
CC receptors that binds the extracellular domain (ECD) of Notch receptor
CC in a cis and trans fashion manner (PubMed:21985982, PubMed:10958687).
CC Following transinteraction, ligand cells produce mechanical force that
CC 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:10958687,
CC PubMed:18676613). Is required for embryonic development and maintenance
CC of adult stem cells in many different tissues and immune systeme; the
CC DLL1-induced Notch signaling is mediated through an intercellular
CC communication that regulates cell lineage, cell specification, cell
CC patterning and morphogenesis through effects on differentiation and
CC proliferation (PubMed:17194759, PubMed:19562077, PubMed:18997111,
CC PubMed:23695674, PubMed:16495313, PubMed:21238454, PubMed:22282195,
CC PubMed:7671806, PubMed:17960184, PubMed:22529374, PubMed:19389377,
CC PubMed:23699523, PubMed:19144989, PubMed:23688253, PubMed:23806616,
CC PubMed:26114479, PubMed:22940113, PubMed:25220152, PubMed:20081190,
CC PubMed:21572390, PubMed:22096075). Plays a role in brain development at
CC different level, namely by regulating neuronal differentiation of
CC neural precursor cells via cell-cell interaction, most likely through
CC the lateral inhibitory system in an endogenous level dependent-manner
CC (PubMed:7671806, PubMed:18997111). During neocortex development, Dll1-
CC Notch signaling transmission is mediated by dynamic interactions
CC between intermediate neurogenic progenitors and radial glia; the cell-
CC cell interactions are mediated via dynamic and transient elongation
CC processes, likely to reactivate/maintain Notch activity in neighboring
CC progenitors, and coordinate progenitor cell division and
CC differentiation across radial and zonal boundaries (PubMed:23699523).
CC During cerebellar development, regulates Bergmann glial monolayer
CC formation and its morphological maturation through a Notch signaling
CC pathway (PubMed:23688253). At the retina and spinal cord level,
CC regulates neurogenesis by preventing the premature differentiation of
CC neural progenitors and also by maintaining progenitors in spinal cord
CC through Notch signaling pathway (PubMed:19389377, PubMed:26114479).
CC Also controls neurogenesis of the neural tube in a progenitor domain-
CC specific fashion along the dorsoventral axis (PubMed:20081190).
CC Maintains quiescence of neural stem cells and plays a role as a fate
CC determinant that segregates asymmetrically to one daughter cell during
CC neural stem cells mitosis, resulting in neuronal differentiation in
CC Dll1-inheriting cell (PubMed:23695674). Plays a role in immune systeme
CC development, namely the development of all T-cells and marginal zone
CC (MZ) B cells (PubMed:15146182, PubMed:19217325). 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). Upon
CC MMP14 cleavage, negatively regulates Notch signaling in haematopoietic
CC progenitor cells to specifically maintain normal B-cell development in
CC bone marrow (PubMed:21572390). Also plays a role during muscle
CC development. During early development, inhibits myoblasts
CC differentiation from the medial dermomyotomal lip and later regulates
CC progenitor cell differentiation (PubMed:17194759). Directly modulates
CC cell adhesion and basal lamina formation in satellite cells through
CC Notch signaling. Maintains myogenic progenitors pool by suppressing
CC differentiation through down-regulation of MYOD1 and is required for
CC satellite cell homing and PAX7 expression (PubMed:22940113). During
CC craniofacial and trunk myogenesis suppresses differentiation of cranial
CC mesoderm-derived and somite-derived muscle via MYOD1 regulation but in
CC cranial mesoderm-derived progenitors, is neither required for satellite
CC cell homing nor for PAX7 expression (PubMed:25220152). Also plays a
CC role during pancreatic cell development. During type B pancreatic cell
CC development, may be involved in the initiation of proximodistal
CC patterning in the early pancreatic epithelium (PubMed:22529374).
CC Stimulates multipotent pancreatic progenitor cells proliferation and
CC pancreatic growth by maintaining HES1 expression and PTF1A protein
CC levels (PubMed:22096075). During fetal stages of development, is
CC required to maintain arterial identity and the responsiveness of
CC arterial endothelial cells for VEGFA through regulation of KDR
CC activation and NRP1 expression (PubMed:19144989). Controls sprouting
CC angiogenesis and subsequent vertical branch formation througth
CC regulation on tip cell differentiation (PubMed:22282195). Negatively
CC regulates goblet cell differentiation in intestine and controls
CC secretory fat commitment through lateral inhibition in small intestine
CC (PubMed:21238454, PubMed:21915337). Plays a role during inner ear
CC development; negatively regulates auditory hair cell differentiation
CC (PubMed:16495313). Plays a role during nephron development through
CC Notch signaling pathway (PubMed:23806616). Regulates growth, blood
CC pressure and energy homeostasis (PubMed:19562077).
CC {ECO:0000250|UniProtKB:O00548, ECO:0000250|UniProtKB:P97677,
CC ECO:0000269|PubMed:10958687, ECO:0000269|PubMed:15146182,
CC ECO:0000269|PubMed:16495313, ECO:0000269|PubMed:17194759,
CC ECO:0000269|PubMed:17960184, ECO:0000269|PubMed:18676613,
CC ECO:0000269|PubMed:18997111, ECO:0000269|PubMed:19144989,
CC ECO:0000269|PubMed:19217325, ECO:0000269|PubMed:19389377,
CC ECO:0000269|PubMed:19562077, ECO:0000269|PubMed:20081190,
CC ECO:0000269|PubMed:21238454, ECO:0000269|PubMed:21572390,
CC ECO:0000269|PubMed:21915337, ECO:0000269|PubMed:21985982,
CC ECO:0000269|PubMed:22096075, ECO:0000269|PubMed:22282195,
CC ECO:0000269|PubMed:22529374, ECO:0000269|PubMed:22940113,
CC ECO:0000269|PubMed:23688253, ECO:0000269|PubMed:23695674,
CC ECO:0000269|PubMed:23699523, ECO:0000269|PubMed:23806616,
CC ECO:0000269|PubMed:25220152, ECO:0000269|PubMed:26114479,
CC ECO:0000269|PubMed:7671806}.
CC -!- SUBUNIT: Homodimer (PubMed:12794186). Interacts with TJP1
CC (PubMed:24715457). Interacts with MMP14; inhibits DLL1-induced Notch
CC signaling (PubMed:21572390). Interacts with MAGI1 (via PDZ domain);
CC forms a complex with CTNNB1 and CDH2 and promotes recruitment to the
CC adherens junction and stabilization on the cell surface
CC (PubMed:15908431). Interacts with PSEN1; undergoes a presenilin-
CC dependent gamma-secretase cleavage that releases a Dll1-intracellular
CC form (PubMed:12794186). Interacts with MFAP5 (PubMed:15788413).
CC Interacts with MIB1 (PubMed:21985982). Interacts with NEURL1B; leads to
CC ubiquitination (PubMed:17003037, PubMed:19723503). Interacts with
CC NEURL1 (PubMed:19723503). Interacts with SYNJ2BP; enhances DLL1 protein
CC stability, and promotes Notch signaling in endothelial cells (By
CC similarity). Interacts with MAGI1, MAGI2, MAGI3 and MPDZ (By
CC similarity). Interacts (via ubiquitin) with EPN1 (via IUM domain);
CC binding with NOTCH1 attached to neighboring cell, promotes ligand
CC ubiquitination and EPN1 interaction, leading to NECD transendocytosis
CC and Notch signaling. Interacts with NOTCH1 (By similarity).
CC {ECO:0000250|UniProtKB:O00548, ECO:0000250|UniProtKB:P97677,
CC ECO:0000269|PubMed:12794186, ECO:0000269|PubMed:15788413,
CC ECO:0000269|PubMed:15908431, ECO:0000269|PubMed:17003037,
CC ECO:0000269|PubMed:19723503, ECO:0000269|PubMed:21572390,
CC ECO:0000269|PubMed:21985982, ECO:0000269|PubMed:24715457}.
CC -!- INTERACTION:
CC Q61483; Q9WVQ1: Magi2; NbExp=3; IntAct=EBI-297125, EBI-297151;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:24715457}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:24715457}. Cell junction, adherens junction
CC {ECO:0000269|PubMed:15908431, ECO:0000269|PubMed:24715457}. Membrane
CC raft {ECO:0000269|PubMed:18676613, ECO:0000269|PubMed:21985982}.
CC Note=Distributed around adherens junction in the apical endfeet through
CC interactions with MAGI1. {ECO:0000269|PubMed:15908431,
CC ECO:0000269|PubMed:24715457}.
CC -!- SUBCELLULAR LOCATION: [Dll1-derived cell-associated form]: Cell
CC membrane {ECO:0000269|PubMed:12794186}.
CC -!- SUBCELLULAR LOCATION: [Dll1-intracellular form]: Nucleus
CC {ECO:0000269|PubMed:12794186}.
CC -!- TISSUE SPECIFICITY: In the embryo, expressed in the paraxial mesoderm
CC and nervous system. Expressed at high levels in adult heart and at
CC lower levels, in adult lung. Highly expressed in satellite cells from
CC masseter and tongue than in satellite cells from leg and extraocular
CC muscle.? (PubMed:25220152). {ECO:0000269|PubMed:25220152,
CC ECO:0000269|PubMed:7671806}.
CC -!- DEVELOPMENTAL STAGE: Expressed until 15 dpc. Expression then decreases
CC and increases again in the adult. In differentiating somites, is
CC expressed at low levels in cells emerging from the dorsomedial lip and
CC subsequently throughout myotomes. In the limb buds, is found in
CC myoblasts and myocytes but not in the progenitor cells
CC (PubMed:17194759). Highly expressed in the endothelium and in the
CC smooth muscle layer starting at 13.5 dpc in arterial vessels, but not
CC in veins. At 12.5 dpc, there is no detectable expression in arteries or
CC veins. This pattern persists until 18.5 dpc (PubMed:19144989). Strongly
CC expressed in developing muscle of tongue, cheek, and in extraocular
CC muscle at 11.5 dpc. Found at 18 dpc and P21 in head muscle
CC (PubMed:25220152). Detected in a subset of cells in the ventricular
CC zone (VZ), the intermediate zone (IZ) and the cortical plate (CP) of
CC neocortex and in the ganglionic eminences at 13.5 dpc. At later stages,
CC such as at 16.5 dpc, found in the VZ and IZ, but at very low levels in
CC the CP of the neocortex (PubMed:18997111). Highly expressed in
CC embryonic cells located in the ventricular zone (VZ) of the retinal
CC neuroepithelium that form clusters; is first detected in cells located
CC in the central retina. As the retina grows, expression spreads
CC peripherally along the expanding neurogenic region, being always absent
CC from the ciliary margin zone (CMZ) (PubMed:19389377).
CC {ECO:0000269|PubMed:17194759, ECO:0000269|PubMed:18997111,
CC ECO:0000269|PubMed:19144989, ECO:0000269|PubMed:19389377,
CC ECO:0000269|PubMed:25220152, ECO:0000269|PubMed:7671806}.
CC -!- INDUCTION: Induced by PTF1A in multipotent pancreatic progenitor cells
CC (PubMed:22096075). Induced by CDX1 and CDX2 during somitogenesis and
CC goblet cell differentiation (PubMed:22015720).
CC {ECO:0000269|PubMed:22015720, ECO:0000269|PubMed:22096075}.
CC -!- PTM: Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis
CC and subsequent degradation. Ubiquitinated; promotes recycling back to
CC the plasma membrane and confers a strong affinity for NOTCH1
CC (PubMed:18676613). Multi-ubiquitination of LYS-613 by MIB1 promotes
CC both cis and trans-interaction with NOTCH1, as well as activation of
CC Notch signaling (PubMed:21985982). Ubiquitinated by NEURL1B
CC (PubMed:17003037). {ECO:0000250|UniProtKB:P10041,
CC ECO:0000269|PubMed:17003037, ECO:0000269|PubMed:18676613,
CC ECO:0000269|PubMed:21985982}.
CC -!- PTM: Phosphorylated in a membrane association-dependent manner.
CC Phosphorylation at Ser-696 requires the presence of Ser-693, whereas
CC phosphorylation at Thr-638 and Ser-693 occurs independently of the
CC other sites. Phosphorylation is required for full ligand activity in
CC vitro and affects surface presentation, ectodomain shedding, and
CC endocytosis. {ECO:0000269|PubMed:24449764}.
CC -!- PTM: Cleaved by MMP14; negatively regulates DLL1-induced Notch
CC signaling in HPCs, modulating B-lymphocyte differentiation in bone
CC marrow (PubMed:21572390). Undergoes two consecutive processing events:
CC a shedding event, partially by ADAM10, that generates a soluble
CC extracellular form and an intracellular membrane-anchored form,
CC followed by a gamma-secretase cleavage releasing an intracellular
CC fragment (PubMed:12794186). {ECO:0000269|PubMed:12794186,
CC ECO:0000269|PubMed:21572390}.
CC -!- PTM: O-fucosylated. Can be elongated to a disaccharide by MFNG.
CC {ECO:0000250|UniProtKB:P97677}.
CC -!- DISRUPTION PHENOTYPE: Heterozygous Dll1 mice mutants are lighter and
CC smaller, with altered fat to lean ratio and have increased blood
CC pressure and a slight bradycardia. The animals have reduced cholesterol
CC and triglyceride levels in blood (PubMed:19562077). Heterozygous Dll1
CC mice mutants and hypomorphic Dll1 mice mutants survive until birth,
CC despite significantly reduced Notch activity (PubMed:17194759).
CC Conditional knockout in inner ear leads to an early and excessive
CC production of hair cells and have vestibular defects (PubMed:16495313).
CC Conditional knockout in a small proportion of neural precursor cells
CC reduces neurogenesis, whereas conditional knockout in a large
CC proportion promotes premature neurogenesis (PubMed:18997111). Hypomorph
CC Dll1 pups mutant survive until birth but are smaller. Conditional
CC knockout Dll1 mice mutant in epidermis, survive and have no gross
CC abnormalities (PubMed:17960184). Hypomorph Dll1 mice mutant survive
CC until birth and have severe skeletal muscle defects (PubMed:19144989).
CC Heterozygous Dll1 mutant embryos show disrupted muscle growth
CC (PubMed:25220152). Conditional knockout Dll1 mice mutant show
CC disorganization of Bergmann fibers, ectopic localization of Bergmann
CC glia in the molecular layer and a reduction in the number of Bergmann
CC glia (PubMed:23688253). {ECO:0000269|PubMed:16495313,
CC ECO:0000269|PubMed:17194759, ECO:0000269|PubMed:17960184,
CC ECO:0000269|PubMed:18997111, ECO:0000269|PubMed:19144989,
CC ECO:0000269|PubMed:19562077, ECO:0000269|PubMed:23688253,
CC ECO:0000269|PubMed:25220152}.
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DR EMBL; X80903; CAA56865.1; -; mRNA.
DR EMBL; AY497019; AAR30869.1; -; Genomic_DNA.
DR EMBL; CH466630; EDL20466.1; -; Genomic_DNA.
DR EMBL; BC057400; AAH57400.1; -; mRNA.
DR EMBL; BC065063; AAH65063.1; -; mRNA.
DR CCDS; CCDS37452.1; -.
DR PIR; I48324; I48324.
DR RefSeq; NP_031891.2; NM_007865.3.
DR AlphaFoldDB; Q61483; -.
DR SMR; Q61483; -.
DR BioGRID; 199232; 7.
DR DIP; DIP-32600N; -.
DR IntAct; Q61483; 8.
DR MINT; Q61483; -.
DR STRING; 10090.ENSMUSP00000014917; -.
DR GlyGen; Q61483; 1 site.
DR iPTMnet; Q61483; -.
DR PhosphoSitePlus; Q61483; -.
DR PaxDb; Q61483; -.
DR PRIDE; Q61483; -.
DR ProteomicsDB; 279687; -.
DR ABCD; Q61483; 5 sequenced antibodies.
DR Antibodypedia; 20091; 564 antibodies from 41 providers.
DR DNASU; 13388; -.
DR Ensembl; ENSMUST00000014917; ENSMUSP00000014917; ENSMUSG00000014773.
DR GeneID; 13388; -.
DR KEGG; mmu:13388; -.
DR UCSC; uc008aoi.2; mouse.
DR CTD; 28514; -.
DR MGI; MGI:104659; Dll1.
DR VEuPathDB; HostDB:ENSMUSG00000014773; -.
DR eggNOG; KOG1217; Eukaryota.
DR GeneTree; ENSGT00940000159781; -.
DR HOGENOM; CLU_012574_1_0_1; -.
DR InParanoid; Q61483; -.
DR OMA; DKPCHQG; -.
DR OrthoDB; 406049at2759; -.
DR PhylomeDB; Q61483; -.
DR TreeFam; TF351835; -.
DR Reactome; R-MMU-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR BioGRID-ORCS; 13388; 4 hits in 71 CRISPR screens.
DR ChiTaRS; Dll1; mouse.
DR PRO; PR:Q61483; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q61483; protein.
DR Bgee; ENSMUSG00000014773; Expressed in interdigital region and 244 other tissues.
DR ExpressionAtlas; Q61483; baseline and differential.
DR Genevisible; Q61483; MM.
DR GO; GO:0005912; C:adherens junction; IDA:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005112; F:Notch binding; IPI:UniProtKB.
DR GO; GO:0097110; F:scaffold protein binding; IPI:UniProtKB.
DR GO; GO:0030957; F:Tat protein binding; ISO:MGI.
DR GO; GO:0009887; P:animal organ morphogenesis; NAS:UniProtKB.
DR GO; GO:0014002; P:astrocyte development; IMP:UniProtKB.
DR GO; GO:0009912; P:auditory receptor cell fate commitment; NAS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; IDA:MGI.
DR GO; GO:0021688; P:cerebellar molecular layer formation; IMP:UniProtKB.
DR GO; GO:0021693; P:cerebellar Purkinje cell layer structural organization; IMP:UniProtKB.
DR GO; GO:0072583; P:clathrin-dependent endocytosis; ISS:UniProtKB.
DR GO; GO:0007386; P:compartment pattern specification; IMP:MGI.
DR GO; GO:0007368; P:determination of left/right symmetry; IMP:MGI.
DR GO; GO:0097102; P:endothelial tip cell fate specification; IMP:UniProtKB.
DR GO; GO:0097009; P:energy homeostasis; IMP:UniProtKB.
DR GO; GO:0001947; P:heart looping; IMP:BHF-UCL.
DR GO; GO:0042386; P:hemocyte differentiation; IDA:MGI.
DR GO; GO:0001701; P:in utero embryonic development; NAS:UniProtKB.
DR GO; GO:0002085; P:inhibition of neuroepithelial cell differentiation; IMP:MGI.
DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IMP:MGI.
DR GO; GO:0048839; P:inner ear development; IMP:MGI.
DR GO; GO:0042472; P:inner ear morphogenesis; NAS:UniProtKB.
DR GO; GO:0046331; P:lateral inhibition; IDA:UniProtKB.
DR GO; GO:0070986; P:left/right axis specification; IMP:BHF-UCL.
DR GO; GO:0072070; P:loop of Henle development; IEP:UniProtKB.
DR GO; GO:0002315; P:marginal zone B cell differentiation; IMP:UniProtKB.
DR GO; GO:0030099; P:myeloid cell differentiation; IDA:MGI.
DR GO; GO:2000726; P:negative regulation of cardiac muscle cell differentiation; IMP:BHF-UCL.
DR GO; GO:0045596; P:negative regulation of cell differentiation; IMP:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0045605; P:negative regulation of epidermal cell differentiation; IMP:UniProtKB.
DR GO; GO:0030857; P:negative regulation of epithelial cell differentiation; IMP:UniProtKB.
DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; IMP:UniProtKB.
DR GO; GO:0045611; P:negative regulation of hemocyte differentiation; IDA:MGI.
DR GO; GO:0045608; P:negative regulation of inner ear auditory receptor cell differentiation; IMP:MGI.
DR GO; GO:0032693; P:negative regulation of interleukin-10 production; ISO:MGI.
DR GO; GO:0045638; P:negative regulation of myeloid cell differentiation; IDA:MGI.
DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IMP:UniProtKB.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IMP:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IBA:GO_Central.
DR GO; GO:0072006; P:nephron development; IMP:UniProtKB.
DR GO; GO:0007399; P:nervous system development; NAS:UniProtKB.
DR GO; GO:0060563; P:neuroepithelial cell differentiation; IMP:MGI.
DR GO; GO:0030182; P:neuron differentiation; IMP:MGI.
DR GO; GO:0048665; P:neuron fate specification; IDA:UniProtKB.
DR GO; GO:0097150; P:neuronal stem cell population maintenance; IMP:UniProtKB.
DR GO; GO:0061314; P:Notch signaling involved in heart development; IC:BHF-UCL.
DR GO; GO:0007219; P:Notch signaling pathway; IMP:UniProtKB.
DR GO; GO:0060853; P:Notch signaling pathway involved in arterial endothelial cell fate commitment; IMP:UniProtKB.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; NAS:UniProtKB.
DR GO; GO:0035265; P:organ growth; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:MGI.
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; IMP:UniProtKB.
DR GO; GO:1903672; P:positive regulation of sprouting angiogenesis; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR GO; GO:0072014; P:proximal tubule development; IEP:UniProtKB.
DR GO; GO:0009954; P:proximal/distal pattern formation; IMP:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; IMP:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; IMP:UniProtKB.
DR GO; GO:0051302; P:regulation of cell division; IMP:UniProtKB.
DR GO; GO:0040008; P:regulation of growth; IMP:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; IMP:UniProtKB.
DR GO; GO:0048631; P:regulation of skeletal muscle tissue growth; IMP:UniProtKB.
DR GO; GO:0014807; P:regulation of somitogenesis; IMP:UniProtKB.
DR GO; GO:1900746; P:regulation of vascular endothelial growth factor signaling pathway; IMP:UniProtKB.
DR GO; GO:0060041; P:retina development in camera-type eye; IMP:UniProtKB.
DR GO; GO:0060042; P:retina morphogenesis in camera-type eye; IMP:UniProtKB.
DR GO; GO:0048630; P:skeletal muscle tissue growth; IMP:UniProtKB.
DR GO; GO:0098773; P:skin epidermis development; IMP:UniProtKB.
DR GO; GO:0001757; P:somite specification; IMP:MGI.
DR GO; GO:0001756; P:somitogenesis; IMP:UniProtKB.
DR GO; GO:0021510; P:spinal cord development; IMP:UniProtKB.
DR GO; GO:0003323; P:type B pancreatic cell development; IMP: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; 4.
DR Pfam; PF07645; EGF_CA; 1.
DR Pfam; PF12661; hEGF; 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; Developmental protein; Differentiation;
KW Direct protein sequencing; Disulfide bond; EGF-like domain; Glycoprotein;
KW Isopeptide bond; Membrane; Notch signaling pathway; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; Signal; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..722
FT /note="Delta-like protein 1"
FT /id="PRO_0000007507"
FT CHAIN 18..535
FT /note="Dll1-soluble form"
FT /evidence="ECO:0000269|PubMed:12794186"
FT /id="PRO_0000434830"
FT CHAIN 536..722
FT /note="Dll1-derived cell-associated form"
FT /evidence="ECO:0000269|PubMed:12794186"
FT /id="PRO_0000434831"
FT CHAIN ?..722
FT /note="Dll1-intracellular form"
FT /evidence="ECO:0000269|PubMed:12794186"
FT /id="PRO_0000434832"
FT TOPO_DOM 18..545
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 546..568
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 569..722
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 176..220
FT /note="DSL"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00377"
FT DOMAIN 225..253
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 256..284
FT /note="EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 291..324
FT /note="EGF-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 331..362
FT /note="EGF-like 4; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 369..401
FT /note="EGF-like 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 408..439
FT /note="EGF-like 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 446..477
FT /note="EGF-like 7; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 484..515
FT /note="EGF-like 8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT REGION 655..697
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 719..722
FT /note="Interaction with MAGI1"
FT /evidence="ECO:0000269|PubMed:15908431"
FT COMPBIAS 680..696
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 527..528
FT /note="Cleavage; by MMP14"
FT /evidence="ECO:0000269|PubMed:21572390"
FT SITE 535..536
FT /note="Cleavage; by ADAM protease"
FT /evidence="ECO:0000269|PubMed:12794186"
FT MOD_RES 638
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:24449764"
FT MOD_RES 693
FT /note="Phosphoserine; by PKB"
FT /evidence="ECO:0000269|PubMed:24449764"
FT MOD_RES 696
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:24449764"
FT CARBOHYD 476
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 178..187
FT /evidence="ECO:0000250"
FT DISULFID 191..203
FT /evidence="ECO:0000250"
FT DISULFID 211..220
FT /evidence="ECO:0000250"
FT DISULFID 225..236
FT /evidence="ECO:0000250"
FT DISULFID 229..242
FT /evidence="ECO:0000250"
FT DISULFID 244..253
FT /evidence="ECO:0000250"
FT DISULFID 256..267
FT /evidence="ECO:0000250"
FT DISULFID 262..273
FT /evidence="ECO:0000250"
FT DISULFID 275..284
FT /evidence="ECO:0000250"
FT DISULFID 291..303
FT /evidence="ECO:0000250"
FT DISULFID 297..313
FT /evidence="ECO:0000250"
FT DISULFID 315..324
FT /evidence="ECO:0000250"
FT DISULFID 331..342
FT /evidence="ECO:0000250"
FT DISULFID 336..351
FT /evidence="ECO:0000250"
FT DISULFID 353..362
FT /evidence="ECO:0000250"
FT DISULFID 369..380
FT /evidence="ECO:0000250"
FT DISULFID 374..390
FT /evidence="ECO:0000250"
FT DISULFID 392..401
FT /evidence="ECO:0000250"
FT DISULFID 408..419
FT /evidence="ECO:0000250"
FT DISULFID 413..428
FT /evidence="ECO:0000250"
FT DISULFID 430..439
FT /evidence="ECO:0000250"
FT DISULFID 446..457
FT /evidence="ECO:0000250"
FT DISULFID 451..466
FT /evidence="ECO:0000250"
FT DISULFID 468..477
FT /evidence="ECO:0000250"
FT DISULFID 484..495
FT /evidence="ECO:0000250"
FT DISULFID 489..504
FT /evidence="ECO:0000250"
FT DISULFID 506..515
FT /evidence="ECO:0000250"
FT CROSSLNK 613
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:21985982"
FT MUTAGEN 613..618
FT /note="KNTNKK->RNTNRR: Highly decreases Notch signaling
FT pathway. Multi-ubiquitination pattern is reduced, although
FT it does appear to be mono-ubiquitinated. Interacts with
FT MIB1. Loss of cis interaction with NOTCH1."
FT /evidence="ECO:0000269|PubMed:21985982"
FT MUTAGEN 613
FT /note="K->R: Highly decreases Notch signaling pathway.
FT Multi-ubiquitination pattern is reduced, although it does
FT appear to be mono-ubiquitinated. Interacts with MIB1. Loss
FT of cis and trans interaction with NOTCH1. Increases its
FT association with lipid raft microdomains."
FT /evidence="ECO:0000269|PubMed:21985982"
FT MUTAGEN 638
FT /note="T->V: Not phosphorylated; when associated with A-693
FT and A-696. Not phosphorylated and doesn't prevent
FT phosphorylation at S-693 and S-696. Reduces NOTCH1
FT transactivation; when associated with A-693 and A-696.
FT Reduces cell surface levels of proteins; when associated
FT with A-693 and A-696. Increases ectodomain shedding; when
FT associated with A-693 and A-696."
FT /evidence="ECO:0000269|PubMed:24449764"
FT MUTAGEN 689
FT /note="K->R: Decreases Notch signaling pathway."
FT /evidence="ECO:0000269|PubMed:21985982"
FT MUTAGEN 693
FT /note="S->A: Not phosphorylated; when associated with V-638
FT and A-696. Not phosphorylated and prevents phosphorylation
FT at S-696. Reduces NOTCH1 transactivation; when associated
FT with V-638 and A-696. Reduces cell surface levels of
FT proteins; when associated with V-638 and A-696. Increases
FT ectodomain shedding; when associated with V-638 and A-696."
FT /evidence="ECO:0000269|PubMed:24449764"
FT MUTAGEN 696
FT /note="S->A: Not phosphorylated; when associated with V-638
FT and A-693. Not phosphorylated and doesn't prevent
FT phosphorylation at T-638 and S-693, Reduces NOTCH1
FT transactivation; when associated with V-638 and A-693.
FT Reduces cell surface levels of proteins; when associated
FT with V-638 and A-693. Increases ectodomain shedding; when
FT associated with V-638 and A-693."
FT /evidence="ECO:0000269|PubMed:24449764"
FT MUTAGEN 699
FT /note="K->R: Decreases Notch signaling pathway."
FT /evidence="ECO:0000269|PubMed:21985982"
FT MUTAGEN 713
FT /note="K->R: Decreases Notch signaling pathway."
FT /evidence="ECO:0000269|PubMed:21985982"
FT CONFLICT 628
FT /note="E -> K (in Ref. 1; CAA56865)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 722 AA; 78449 MW; 9D570B9DC7EEC75E CRC64;
MGRRSALALA VVSALLCQVW SSGVFELKLQ EFVNKKGLLG NRNCCRGGSG PPCACRTFFR
VCLKHYQASV SPEPPCTYGS AVTPVLGVDS FSLPDGAGID PAFSNPIRFP FGFTWPGTFS
LIIEALHTDS PDDLATENPE RLISRLTTQR HLTVGEEWSQ DLHSSGRTDL RYSYRFVCDE
HYYGEGCSVF CRPRDDAFGH FTCGDRGEKM CDPGWKGQYC TDPICLPGCD DQHGYCDKPG
ECKCRVGWQG RYCDECIRYP GCLHGTCQQP WQCNCQEGWG GLFCNQDLNY CTHHKPCRNG
ATCTNTGQGS YTCSCRPGYT GANCELEVDE CAPSPCKNGA SCTDLEDSFS CTCPPGFYGK
VCELSAMTCA DGPCFNGGRC SDNPDGGYTC HCPLGFSGFN CEKKMDLCGS SPCSNGAKCV
DLGNSYLCRC QAGFSGRYCE DNVDDCASSP CANGGTCRDS VNDFSCTCPP GYTGKNCSAP
VSRCEHAPCH NGATCHQRGQ RYMCECAQGY GGPNCQFLLP EPPPGPMVVD LSERHMESQG
GPFPWVAVCA GVVLVLLLLL GCAAVVVCVR LKLQKHQPPP EPCGGETETM NNLANCQREK
DVSVSIIGAT QIKNTNKKAD FHGDHGAEKS SFKVRYPTVD YNLVRDLKGD EATVRDTHSK
RDTKCQSQSS AGEEKIAPTL RGGEIPDRKR PESVYSTSKD TKYQSVYVLS AEKDECVIAT
EV
