https://www.ncbi.nlm.nih.gov/pubmed/30455992
Bone Res. 2018 Nov 10;6:32. doi: 10.1038/s41413-018-0030-y. eCollection 2018.
NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts.
Ye L1,
Lou F1,
Yu F1,
Zhang D1,
Wang C1,
Wu F1,
Li X1,
Ping Y1,
Yang X1,
Yang J1,
Chen D1,
Gao B1,
Huang D1,
Liu P2.
Abstract
Adaptoriprotieini NUMB osallistuu asymmteriseen solunjakautumiseen ja solukohtalon määräämiseen ja se on tunnistettu NOTCH- antagonistina.
Aiemmissa tutkimuksissa on osoitautunut, että Notch-aktivaatio osteoblasteissa vaikuttaa korkeaa luumassaa.
Tässä tutkimuksessa kuitenkin hiiren osteopeninen fenotyyppi havaittiin 9-viikkoisessa hiiressä käyttämällä osteoblastipesifistä Col1alfa-2.3-Cre , joka teki ablaation sekä Numb:iin että sen homolgiin Numbl. Trabekulaarinen luumassa väheni dramaattisesti kun taas kortikaalinen luumassa ei vaikuttunut. Tässä ei NOTCH signaali aktivoitunut, kun taas PTEN (PI3kinasien defosforyloija) oli koholla vaimentaen PKB (Akt) .
Ubikitinaatiomenetelmällä selvisi, että NUMB saattaa fysiologisesti edistää PTEN-ubikitinaatiota, jos läsnä on erästä neuronin esiasteessa kehityksellisti alassäätynyttä proteiinia.
Lisäksi Numb/Numbl vaje aktivoi Hedgehog tien GLII- kautta. Tämän prosessin vaikuttavan NFKB tien suhdetta ostoprotegeriiniin, joka lisää osteoklastien erilaistumista ja luun resorptiota . Johtopäätös täten on, että NUMB ja NUMBL voivat vaikuttaa luun homeostaassiin.
- The adaptor protein NUMB
is involved in asymmetric division and cell fate determination and
recognized as an antagonist of Notch. Previous studies have proved that
Notch activation in osteoblasts contributes to a high bone mass. In this
study, however, an osteopenic phenotype was found in 9-week-old mice
using osteoblastic specific Col1a1-2.3-Cre to ablate both Numb and its homologue Numbl
. The trabecular bone mass decreased dramatically while the cortical
bone mass was unaffected. Here, the Notch signal was not activated,
while the tensin homologue deleted on human chromosome 10 (PTEN), which
dephosphorylates phosphatidylinositide 3-kinases, was elevated,
attenuating protein kinase B (Akt). The ubiquitination assay revealed
that NUMB may
physiologically promote PTEN ubiquitination in the presence of neural
precursor cell-expressed developmentally downregulated protein 4-1. In
addition, the deficiency of Numb/Numbl
also activated the Hedgehog pathway through GLI1. This process was
found to improve the ratio of the receptor activator of nuclear
factor-kB ligand to osteoprotegerin, which enhanced the differentiation
of osteoclasts and bone resorption . In conclusion, this study provides
an insight into new functons of NUMB and NUMBL on bone homeostasis.
Gene NUMB (14q24.2.-q24.3)
https://www.ncbi.nlm.nih.gov/gene/8650
- S171; C14orf41; c14_5527
- Summary
- The protein encoded by this gene plays a role in the
determination of cell fates during development. The encoded protein,
whose degradation is induced in a proteasome-dependent manner by MDM2,
is a membrane-bound protein that has been shown to associate with EPS15,
LNX1, and NOTCH1. Alternative splicing results in multiple transcript
variants. [provided by RefSeq, Feb 2016]
- Expression
- Ubiquitous expression in lung (RPKM 25.7), gall bladder (RPKM 21.4) and 25 other tissues See more
- Preferred Names
- protein numb homolog
- Names
- h-Numb
- numb homolog
Conserved Domains (2) summary
- cd01268
Location:23 → 168
- PTB_Numb; Numb Phosphotyrosine-binding (PTB) domain
- pfam06311
Location:258 → 338
- NumbF; NUM
LOCUS NP_001005743 651 aa linear PRI 11-NOV-2018
DEFINITION protein numb homolog isoform 1 [Homo sapiens].
ACCESSION NP_001005743
VERSION NP_001005743.1
DBSOURCE REFSEQ: accession NM_001005743.1
KEYWORDS RefSeq.
SOURCE Homo sapiens (human)
ORGANISM Homo sapiens
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
REFERENCE 1 (residues 1 to 651)
AUTHORS Zhang C, Kang Y, Ma R, Chen F, Chen F and Dong X.
TITLE Expression of Numb and Gli1 in malignant pleural mesothelioma and
their clinical significance
JOURNAL J Cancer Res Ther 14 (5), 970-976 (2018)
PUBMED 30197333
REMARK GeneRIF: The results provide new evidence of Numb and Gli1 on the
clinical characteristics of Malignant pleural mesothelioma, which
may be helpful in clinical diagnosis and targeted therapy. Further
research with larger sample size is needed
REFERENCE 2 (residues 1 to 651)
AUTHORS Schuring AN, Dahlhues B, Korte A, Kiesel L, Titze U, Heitkotter B,
Ruckert C and Gotte M.
TITLE The endometrial stem cell markers notch-1 and numb are associated
with endometriosis
JOURNAL Reprod. Biomed. Online 36 (3), 294-301 (2018)
PUBMED 29398419
REMARK GeneRIF: High NUMB expression is associated with endometriosis.
REFERENCE 3 (residues 1 to 651)
AUTHORS Colaluca IN, Basile A, Freiburger L, D'Uva V, Disalvatore D, Vecchi
M, Confalonieri S, Tosoni D, Cecatiello V, Malabarba MG, Yang CJ,
Kainosho M, Sattler M, Mapelli M, Pece S and Di Fiore PP.
TITLE A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement
of Numb in breast cancer
JOURNAL J. Cell Biol. 217 (2), 745-762 (2018)
PUBMED 29269425
REFERENCE 4 (residues 1 to 651)
AUTHORS Guo Y, Zhang K, Cheng C, Ji Z, Wang X, Wang M, Chu M, Tang DG, Zhu
HH and Gao WQ.
TITLE Numb(-/low) Enriches a Castration-Resistant Prostate Cancer Cell
Subpopulation Associated with Enhanced Notch and Hedgehog Signaling
JOURNAL Clin. Cancer Res. 23 (21), 6744-6756 (2017)
PUBMED 28751447
REMARK GeneRIF: Numb(-/low) prostate cancer cells were smaller and
quiescent, preferentially expressed Notch and Hedgehog downstream
and stem-cell-associated genes, and associated with a greater
resistance to androgen-deprivation therapy
REFERENCE 5 (residues 1 to 651)
AUTHORS Bocci F, Jolly MK, Tripathi SC, Aguilar M, Hanash SM, Levine H and
Onuchic JN.
TITLE Numb prevents a complete epithelial-mesenchymal transition by
modulating Notch signalling
JOURNAL J R Soc Interface 14 (136) (2017)
PUBMED 29187638
REMARK GeneRIF: Numb is associated with modulation of Notch-driven
epithelial-mesenchymal transition.
REFERENCE 6 (residues 1 to 651)
AUTHORS Dho SE, Jacob S, Wolting CD, French MB, Rohrschneider LR and
McGlade CJ.
TITLE The mammalian numb phosphotyrosine-binding domain. Characterization
of binding specificity and identification of a novel PDZ
domain-containing numb binding protein, LNX
JOURNAL J. Biol. Chem. 273 (15), 9179-9187 (1998)
PUBMED 9535908
REFERENCE 7 (residues 1 to 651)
AUTHORS Salcini AE, Confalonieri S, Doria M, Santolini E, Tassi E,
Minenkova O, Cesareni G, Pelicci PG and Di Fiore PP.
TITLE Binding specificity and in vivo targets of the EH domain, a novel
protein-protein interaction module
JOURNAL Genes Dev. 11 (17), 2239-2249 (1997)
PUBMED 9303539
REFERENCE 8 (residues 1 to 651)
AUTHORS Zhong W, Feder JN, Jiang MM, Jan LY and Jan YN.
TITLE Asymmetric localization of a mammalian numb homolog during mouse
cortical neurogenesis
JOURNAL Neuron 17 (1), 43-53 (1996)
PUBMED 8755477
REFERENCE 9 (residues 1 to 651)
AUTHORS Wong WT, Schumacher C, Salcini AE, Romano A, Castagnino P, Pelicci
PG and Di Fiore PP.
TITLE A protein-binding domain, EH, identified in the receptor tyrosine
kinase substrate Eps15 and conserved in evolution
JOURNAL Proc. Natl. Acad. Sci. U.S.A. 92 (21), 9530-9534 (1995)
PUBMED 7568168
REFERENCE 10 (residues 1 to 651)
AUTHORS Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M,
Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC,
Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I,
Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA,
Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE,
Rommens JM and St George-Hyslop PH.
TITLE Cloning of a gene bearing missense mutations in early-onset
familial Alzheimer's disease
JOURNAL Nature 375 (6534), 754-760 (1995)
PUBMED 7596406
COMMENT REVIEWED REFSEQ: This record has been curated by NCBI staff. The
reference sequence was derived from BC068476.1, AF171938.1 and
AA872908.1.
This sequence is a reference standard in the RefSeqGene project.
Summary: The protein encoded by this gene plays a role in the
determination of cell fates during development. The encoded
protein, whose degradation is induced in a proteasome-dependent
manner by MDM2, is a membrane-bound protein that has been shown to
associate with EPS15, LNX1, and NOTCH1. Alternative splicing
results in multiple transcript variants. [provided by RefSeq, Feb
2016].
Transcript Variant: This variant (1) represents the longest
transcript and encodes the longest isoform (1).
Publication Note: This RefSeq record includes a subset of the
publications that are available for this gene. Please see the Gene
record to access additional publications.
##Evidence-Data-START##
Transcript exon combination :: AF171938.1 [ECO:0000332]
RNAseq introns :: mixed/partial sample support
SAMEA1965299, SAMEA1966682
[ECO:0000350]
##Evidence-Data-END##
FEATURES Location/Qualifiers
source 1..651
/organism="Homo sapiens"
/db_xref="taxon:9606"
/chromosome="14"
/map="14q24.2-q24.3"
Protein 1..651
/product="protein numb homolog isoform 1"
/note="protein numb homolog; h-Numb"
/calculated_mol_wt=70673
Region 23..168
/region_name="PTB_Numb"
/note="Numb Phosphotyrosine-binding (PTB) domain; cd01268"
/db_xref="CDD:241298"
Site order(42,125,145)
/site_type="other"
/note="putative phosphoinositide binding site [chemical
binding]"
/db_xref="CDD:241298"
Site order(55,116..119,155,159,162,166)
/site_type="other"
/note="peptide binding site [polypeptide binding]"
/db_xref="CDD:241298"
Site 194
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine. {ECO:0000244|PubMed:23186163};
propagated from UniProtKB/Swiss-Prot (P49757.2)"
Site 243
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphothreonine. {ECO:0000250|UniProtKB:Q9QZS3};
propagated from UniProtKB/Swiss-Prot (P49757.2)"
Site 244
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine. {ECO:0000244|PubMed:18669648};
propagated from UniProtKB/Swiss-Prot (P49757.2)"
Region 258..338
/region_name="NumbF"
/note="NUMB domain; pfam06311"
/db_xref="CDD:283874"
Site 276
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine, by CaMK1.
{ECO:0000250|UniProtKB:Q2LC84}; propagated from
UniProtKB/Swiss-Prot (P49757.2)"
Site 295
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine, by CaMK1.
{ECO:0000250|UniProtKB:Q2LC84}; propagated from
UniProtKB/Swiss-Prot (P49757.2)"
Site 425
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine. {ECO:0000244|PubMed:23186163};
propagated from UniProtKB/Swiss-Prot (P49757.2)"
Site 436
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphothreonine. {ECO:0000244|PubMed:23186163};
propagated from UniProtKB/Swiss-Prot (P49757.2)"
Site 438
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine. {ECO:0000244|PubMed:23186163,
ECO:0000244|PubMed:24275569}; propagated from
UniProtKB/Swiss-Prot (P49757.2)"
Site 634
/site_type="other"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine. {ECO:0000244|PubMed:16964243,
ECO:0000244|PubMed:23186163}; propagated from
UniProtKB/Swiss-Prot (P49757.2)"
CDS 1..651
/gene="NUMB"
/gene_synonym="C14orf41; c14_5527; S171"
/coded_by="NM_001005743.1:321..2276"
/note="isoform 1 is encoded by transcript variant 1"
/db_xref="CCDS:CCDS32116.1"
/db_xref="GeneID:8650"
/db_xref="HGNC:HGNC:8060"
/db_xref="MIM:603728"
ORIGIN
1 mnklrqsfrr kkdvyvpeas rphqwqtdee gvrtgkcsfp vkylghvevd esrgmhiced
61 avkrlkaerk ffkgffgktg kkavkavlwv sadglrvvde ktkdlivdqt iekvsfcapd
121 rnfdrafsyi crdgttrrwi chcfmavkdt gerlshavgc afaaclerkq krekecgvta
181 tfdasrttft regsfrvtta teqaereeim kqmqdakkae tdkivvgssv apgntapsps
241 sptsptsdat tslemnnpha iprrhapieq larqgsfrgf palsqkmspf krqlslrine
301 lpstmqrktd fpiknavpev egeaesissl csqitnafst pedpfssapm tkpvtvvapq
361 sptfqangtd safhvlakpa htalapvamp vretnpwaha pdaankeiaa tcsgtewgqs
421 sgaaspglfq aghrrtpsea drwleevsks vraqqpqasa aplqpvlqpp pptaisqpas
481 pfqgnaflts qpvpvgvvpa lqpafvpaqs ypvangmpyp apnvpvvgit psqmvanvfg
541 taghpqaahp hqspslvrqq tfphyeassa ttspffkppa qhlngsaafn gvddgrlasa
601 drhtevptgt cpvdpfeaqw aalenkskqr tnpsptnpfs sdlqktfeie l
//
Related articles in PubMed
-
Numb prevents a complete epithelial-mesenchymal transition (EMT) by modulating Notch signalling.
Bocci F, et al. J R Soc Interface, 2017 Nov. PMID 29187638, Free PMC Article
-
Numb-/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling.
Guo Y, et al. Clin Cancer Res, 2017 Nov 1. PMID 28751447
-
Numb positively regulates autophagic flux via regulating lysosomal function.
Sun H, et al. Biochem Biophys Res Commun, 2017 Sep 23. PMID 28720501
-
Numb had anti-tumor effects in prostatic cancer.
Sun J, et al. Biomed Pharmacother, 2017 Aug. PMID 28531799
-
Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers.
Tosoni D, et al. EMBO Mol Med, 2017 May. PMID 28298340, Free PMC Article
