ID   NUMBL_HUMAN             Reviewed;         609 AA.
AC   Q9Y6R0; Q7Z4J9;
DT   01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1999, sequence version 1.
DT   27-MAR-2024, entry version 190.
DE   RecName: Full=Numb-like protein;
DE   AltName: Full=Numb-related protein;
DE            Short=Numb-R;
GN   Name=NUMBL;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9303539; DOI=10.1101/gad.11.17.2239;
RA   Salcini A.E., Confalonieri S., Doria M., Santolini E., Tassi E.,
RA   Minenkova O., Cesareni G., Pelicci P.G., Di Fiore P.P.;
RT   "Binding specificity and in vivo targets of the EH domain, a novel protein-
RT   protein interaction module.";
RL   Genes Dev. 11:2239-2249(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 9-609.
RC   TISSUE=Eye;
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   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 42-609.
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [5]
RP   FUNCTION, INTERACTION WITH MAP3K7IP2, AND SUBCELLULAR LOCATION.
RX   PubMed=18299187; DOI=10.1016/j.cellsig.2008.01.015;
RA   Ma Q., Zhou L., Shi H., Huo K.;
RT   "NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-
RT   kappaB activation.";
RL   Cell. Signal. 20:1044-1051(2008).
RN   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-279, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [7]
RP   FUNCTION, AND INTERACTION WITH TRAF6.
RX   PubMed=20079715; DOI=10.1016/j.bbrc.2010.01.037;
RA   Zhou L., Ma Q., Shi H., Huo K.;
RT   "NUMBL interacts with TRAF6 and promotes the degradation of TRAF6.";
RL   Biochem. Biophys. Res. Commun. 392:409-414(2010).
RN   [8]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [9]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-224; SER-228 AND SER-263, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [10]
RP   X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 60-204.
RG   Structural genomics consortium (SGC);
RT   "Human numb-like protein, phosphotyrosine interaction domain.";
RL   Submitted (FEB-2009) to the PDB data bank.
CC   -!- FUNCTION: Plays a role in the process of neurogenesis. Required
CC       throughout embryonic neurogenesis to maintain neural progenitor cells,
CC       also called radial glial cells (RGCs), by allowing their daughter cells
CC       to choose progenitor over neuronal cell fate. Not required for the
CC       proliferation of neural progenitor cells before the onset of embryonic
CC       neurogenesis. Also required postnatally in the subventricular zone
CC       (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal
CC       wall integrity. Negative regulator of NF-kappa-B signaling pathway. The
CC       inhibition of NF-kappa-B activation is mediated at least in part, by
CC       preventing MAP3K7IP2 to interact with polyubiquitin chains of TRAF6 and
CC       RIPK1 and by stimulating the 'Lys-48'-linked polyubiquitination and
CC       degradation of TRAF6 in cortical neurons. {ECO:0000269|PubMed:18299187,
CC       ECO:0000269|PubMed:20079715}.
CC   -!- SUBUNIT: Interacts (via PTB domain) with MAP3K7IP2 (via C-terminal).
CC       Interacts (via C-terminal) with TRAF6 (via TRAF domains). Associates
CC       with EPS15 and NOTCH1. {ECO:0000269|PubMed:18299187,
CC       ECO:0000269|PubMed:20079715}.
CC   -!- INTERACTION:
CC       Q9Y6R0; Q00535: CDK5; NbExp=3; IntAct=EBI-945925, EBI-1041567;
CC       Q9Y6R0; O94985-2: CLSTN1; NbExp=3; IntAct=EBI-945925, EBI-16041593;
CC       Q9Y6R0; P00533: EGFR; NbExp=2; IntAct=EBI-945925, EBI-297353;
CC       Q9Y6R0; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-945925, EBI-9090282;
CC       Q9Y6R0; Q9NWB1: RBFOX1; NbExp=2; IntAct=EBI-945925, EBI-945906;
CC       Q9Y6R0; Q6PJ21: SPSB3; NbExp=5; IntAct=EBI-945925, EBI-3937206;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Note=Symmetrically
CC       distributed throughout the cytoplasm in non dividing neuroblasts of the
CC       CNS. {ECO:0000250}.
CC   -!- DOMAIN: The PTB domain is necessary for the inhibition of MAP3K7IP2-
CC       mediated activation of NF-kappa-B.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF015041; AAD01549.1; -; mRNA.
DR   EMBL; BC001794; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; BT009807; AAP88809.1; -; mRNA.
DR   CCDS; CCDS12561.1; -.
DR   RefSeq; NP_001276908.1; NM_001289979.1.
DR   RefSeq; NP_001276909.1; NM_001289980.2.
DR   RefSeq; NP_004747.1; NM_004756.4.
DR   PDB; 3F0W; X-ray; 2.70 A; A=60-204.
DR   PDBsum; 3F0W; -.
DR   AlphaFoldDB; Q9Y6R0; -.
DR   SMR; Q9Y6R0; -.
DR   BioGRID; 114677; 112.
DR   ELM; Q9Y6R0; -.
DR   IntAct; Q9Y6R0; 50.
DR   MINT; Q9Y6R0; -.
DR   STRING; 9606.ENSP00000252891; -.
DR   GlyCosmos; Q9Y6R0; 1 site, 1 glycan.
DR   GlyGen; Q9Y6R0; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q9Y6R0; -.
DR   MetOSite; Q9Y6R0; -.
DR   PhosphoSitePlus; Q9Y6R0; -.
DR   BioMuta; NUMBL; -.
DR   DMDM; 14194976; -.
DR   EPD; Q9Y6R0; -.
DR   jPOST; Q9Y6R0; -.
DR   MassIVE; Q9Y6R0; -.
DR   MaxQB; Q9Y6R0; -.
DR   PaxDb; 9606-ENSP00000252891; -.
DR   PeptideAtlas; Q9Y6R0; -.
DR   ProteomicsDB; 86771; -.
DR   Pumba; Q9Y6R0; -.
DR   Antibodypedia; 30612; 304 antibodies from 32 providers.
DR   DNASU; 9253; -.
DR   Ensembl; ENST00000252891.8; ENSP00000252891.3; ENSG00000105245.9.
DR   GeneID; 9253; -.
DR   KEGG; hsa:9253; -.
DR   MANE-Select; ENST00000252891.8; ENSP00000252891.3; NM_004756.5; NP_004747.1.
DR   UCSC; uc002oon.5; human.
DR   AGR; HGNC:8061; -.
DR   CTD; 9253; -.
DR   DisGeNET; 9253; -.
DR   GeneCards; NUMBL; -.
DR   HGNC; HGNC:8061; NUMBL.
DR   HPA; ENSG00000105245; Low tissue specificity.
DR   MIM; 604018; gene.
DR   neXtProt; NX_Q9Y6R0; -.
DR   OpenTargets; ENSG00000105245; -.
DR   PharmGKB; PA31846; -.
DR   VEuPathDB; HostDB:ENSG00000105245; -.
DR   eggNOG; KOG3537; Eukaryota.
DR   GeneTree; ENSGT00940000160957; -.
DR   InParanoid; Q9Y6R0; -.
DR   OMA; PWMSRSA; -.
DR   OrthoDB; 2913102at2759; -.
DR   PhylomeDB; Q9Y6R0; -.
DR   TreeFam; TF314159; -.
DR   PathwayCommons; Q9Y6R0; -.
DR   SignaLink; Q9Y6R0; -.
DR   BioGRID-ORCS; 9253; 111 hits in 1157 CRISPR screens.
DR   ChiTaRS; NUMBL; human.
DR   EvolutionaryTrace; Q9Y6R0; -.
DR   GeneWiki; NUMBL; -.
DR   GenomeRNAi; 9253; -.
DR   Pharos; Q9Y6R0; Tbio.
DR   PRO; PR:Q9Y6R0; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; Q9Y6R0; Protein.
DR   Bgee; ENSG00000105245; Expressed in pancreatic ductal cell and 186 other cell types or tissues.
DR   ExpressionAtlas; Q9Y6R0; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0034332; P:adherens junction organization; IEA:Ensembl.
DR   GO; GO:0007409; P:axonogenesis; IEA:Ensembl.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:UniProtKB.
DR   GO; GO:0021670; P:lateral ventricle development; ISS:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR   GO; GO:0021849; P:neuroblast division in subventricular zone; ISS:UniProtKB.
DR   GO; GO:0050769; P:positive regulation of neurogenesis; ISS:UniProtKB.
DR   GO; GO:0019538; P:protein metabolic process; IDA:UniProtKB.
DR   CDD; cd01268; PTB_Numb; 1.
DR   Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1.
DR   InterPro; IPR016698; Numb/numb-like.
DR   InterPro; IPR010449; Numb_domain.
DR   InterPro; IPR011993; PH-like_dom_sf.
DR   InterPro; IPR006020; PTB/PI_dom.
DR   PANTHER; PTHR47368; NUMB; 1.
DR   PANTHER; PTHR47368:SF4; NUMB-LIKE PROTEIN; 1.
DR   Pfam; PF06311; NumbF; 1.
DR   Pfam; PF00640; PID; 1.
DR   PIRSF; PIRSF017607; Numb/numb-like; 1.
DR   SMART; SM00462; PTB; 1.
DR   SUPFAM; SSF50729; PH domain-like; 1.
DR   PROSITE; PS01179; PID; 1.
DR   Genevisible; Q9Y6R0; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Cytoplasm; Developmental protein; Neurogenesis;
KW   Phosphoprotein; Reference proteome; Ubl conjugation pathway.
FT   CHAIN           1..609
FT                   /note="Numb-like protein"
FT                   /id="PRO_0000057999"
FT   DOMAIN          74..223
FT                   /note="PID"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT   REGION          1..68
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          223..283
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          372..421
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          434..464
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          537..609
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        15..29
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        52..68
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        434..451
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        542..573
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         224
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         228
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         263
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         279
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         411
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08919"
FT   TURN            64..66
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   HELIX           67..74
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          78..91
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   HELIX           96..107
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          114..120
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          122..129
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   TURN            130..132
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          135..140
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   HELIX           141..143
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          144..149
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          156..163
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   TURN            164..167
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   STRAND          168..179
FT                   /evidence="ECO:0007829|PDB:3F0W"
FT   HELIX           181..201
FT                   /evidence="ECO:0007829|PDB:3F0W"
SQ   SEQUENCE   609 AA;  64891 MW;  69458D161B60F4B4 CRC64;
     MSRSAAASGG PRRPERHLPP APCGAPGPPE TCRTEPDGAG TMNKLRQSLR RRKPAYVPEA
     SRPHQWQADE DAVRKGTCSF PVRYLGHVEV EESRGMHVCE DAVKKLKAMG RKSVKSVLWV
     SADGLRVVDD KTKDLLVDQT IEKVSFCAPD RNLDKAFSYI CRDGTTRRWI CHCFLALKDS
     GERLSHAVGC AFAACLERKQ RREKECGVTA AFDASRTSFA REGSFRLSGG GRPAEREAPD
     KKKAEAAAAP TVAPGPAQPG HVSPTPATTS PGEKGEAGTP VAAGTTAAAI PRRHAPLEQL
     VRQGSFRGFP ALSQKNSPFK RQLSLRLNEL PSTLQRRTDF QVKGTVPEME PPGAGDSDSI
     NALCTQISSS FASAGAPAPG PPPATTGTSA WGEPSVPPAA AFQPGHKRTP SEAERWLEEV
     SQVAKAQQQQ QQQQQQQQQQ QQQQQQAASV APVPTMPPAL QPFPAPVGPF DAAPAQVAVF
     LPPPHMQPPF VPAYPGLGYP PMPRVPVVGI TPSQMVANAF CSAAQLQPQP ATLLGKAGAF
     PPPAIPSAPG SQARPRPNGA PWPPEPAPAP APELDPFEAQ WAALEGKATV EKPSNPFSGD
     LQKTFEIEL
//