NOTCH3

NOTCH3
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4ZLP, 5CZX, 5CZV
Identifikatori
Aliasi	NOTCH3
Vanjski ID-jevi	OMIM: 600276 MGI: 99460 HomoloGene: 376 GeneCards: NOTCH3
Lokacija gena (čovjek)
Hrom.	Hromosom 19 (čovjek)
Kraj	15,200,995 bp
Lokacija gena (miš)
Hrom.	Hromosom 17 (miš)
Kraj	32,385,826 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• calcium ion binding; • GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje enzima; • cadherin binding; • vezivanje identičnih proteina; • signaling receptor activity;
Ćelijska komponenta	• integral component of membrane; • endoplasmic reticulum membrane; • membrana; • Golđijeva membrana; • receptor complex; • ćelijska membrana; • nukleoplazma; • extracellular region; • actin cytoskeleton; • jedro; • citosol; • cell surface;
Biološki proces	• Notch signaling pathway; • Ćelijska diferencijacija; • GO:0009373 regulation of transcription, DNA-templated; • negative regulation of neuron differentiation; • negative regulation of cell differentiation; • glomerular capillary formation; • GO:1901227 negative regulation of transcription by RNA polymerase II; • transcription, DNA-templated; • multicellular organism development; • artery morphogenesis; • forebrain development; • neuron fate commitment; • transcription initiation from RNA polymerase II promoter; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • positive regulation of smooth muscle cell proliferation; • GO:0090343, GO:0090342 regulation of developmental process; • positive regulation of transcription of Notch receptor target; • Notch receptor processing, ligand-dependent; • negative regulation of Notch signaling pathway;
	Izvori:Amigo / QuickGO
Ortolozi
	4854
	18131
	ENSG00000074181
	ENSMUSG00000038146
	Q9UM47
	Q61982
	NM_000435
	NM_008716
	NP_000426
	NP_032742
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Neurogeni lokus zareznog homologa proteina 3 je protein koji je kod ljudi kodiran genom NOTCH3.^[5]^[6]

Aminokiselinska sekvenca

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

10	20	30	40	50
MGPGARGRRR	RRRPMSPPPP	PPPVRALPLL	LLLAGPGAAA	PPCLDGSPCA
NGGRCTQLPS	REAACLCPPG	WVGERCQLED	PCHSGPCAGR	GVCQSSVVAG
TARFSCRCPR	GFRGPDCSLP	DPCLSSPCAH	GARCSVGPDG	RFLCSCPPGY
QGRSCRSDVD	ECRVGEPCRH	GGTCLNTPGS	FRCQCPAGYT	GPLCENPAVP
CAPSPCRNGG	TCRQSGDLTY	DCACLPGFEG	QNCEVNVDDC	PGHRCLNGGT
CVDGVNTYNC	QCPPEWTGQF	CTEDVDECQL	QPNACHNGGT	CFNTLGGHSC
VCVNGWTGES	CSQNIDDCAT	AVCFHGATCH	DRVASFYCAC	PMGKTGLLCH
LDDACVSNPC	HEDAICDTNP	VNGRAICTCP	PGFTGGACDQ	DVDECSIGAN
PCEHLGRCVN	TQGSFLCQCG	RGYTGPRCET	DVNECLSGPC	RNQATCLDRI
GQFTCICMAG	FTGTYCEVDI	DECQSSPCVN	GGVCKDRVNG	FSCTCPSGFS
GSTCQLDVDE	CASTPCRNGA	KCVDQPDGYE	CRCAEGFEGT	LCDRNVDDCS
PDPCHHGRCV	DGIASFSCAC	APGYTGTRCE	SQVDECRSQP	CRHGGKCLDL
VDKYLCRCPS	GTTGVNCEVN	IDDCASNPCT	FGVCRDGINR	YDCVCQPGFT
GPLCNVEINE	CASSPCGEGG	SCVDGENGFR	CLCPPGSLPP	LCLPPSHPCA
HEPCSHGICY	DAPGGFRCVC	EPGWSGPRCS	QSLARDACES	QPCRAGGTCS
SDGMGFHCTC	PPGVQGRQCE	LLSPCTPNPC	EHGGRCESAP	GQLPVCSCPQ
GWQGPRCQQD	VDECAGPAPC	GPHGICTNLA	GSFSCTCHGG	YTGPSCDQDI
NDCDPNPCLN	GGSCQDGVGS	FSCSCLPGFA	GPRCARDVDE	CLSNPCGPGT
CTDHVASFTC	TCPPGYGGFH	CEQDLPDCSP	SSCFNGGTCV	DGVNSFSCLC
RPGYTGAHCQ	HEADPCLSRP	CLHGGVCSAA	HPGFRCTCLE	SFTGPQCQTL
VDWCSRQPCQ	NGGRCVQTGA	YCLCPPGWSG	RLCDIRSLPC	REAAAQIGVR
LEQLCQAGGQ	CVDEDSSHYC	VCPEGRTGSH	CEQEVDPCLA	QPCQHGGTCR
GYMGGYMCEC	LPGYNGDNCE	DDVDECASQP	CQHGGSCIDL	VARYLCSCPP
GTLGVLCEIN	EDDCGPGPPL	DSGPRCLHNG	TCVDLVGGFR	CTCPPGYTGL
RCEADINECR	SGACHAAHTR	DCLQDPGGGF	RCLCHAGFSG	PRCQTVLSPC
ESQPCQHGGQ	CRPSPGPGGG	LTFTCHCAQP	FWGPRCERVA	RSCRELQCPV
GVPCQQTPRG	PRCACPPGLS	GPSCRSFPGS	PPGASNASCA	AAPCLHGGSC
RPAPLAPFFR	CACAQGWTGP	RCEAPAAAPE	VSEEPRCPRA	ACQAKRGDQR
CDRECNSPGC	GWDGGDCSLS	VGDPWRQCEA	LQCWRLFNNS	RCDPACSSPA
CLYDNFDCHA	GGRERTCNPV	YEKYCADHFA	DGRCDQGCNT	EECGWDGLDC
ASEVPALLAR	GVLVLTVLLP	PEELLRSSAD	FLQRLSAILR	TSLRFRLDAH
GQAMVFPYHR	PSPGSEPRAR	RELAPEVIGS	VVMLEIDNRL	CLQSPENDHC
FPDAQSAADY	LGALSAVERL	DFPYPLRDVR	GEPLEPPEPS	VPLLPLLVAG
AVLLLVILVL	GVMVARRKRE	HSTLWFPEGF	SLHKDVASGH	KGRREPVGQD
ALGMKNMAKG	ESLMGEVATD	WMDTECPEAK	RLKVEEPGMG	AEEAVDCRQW
TQHHLVAADI	RVAPAMALTP	PQGDADADGM	DVNVRGPDGF	TPLMLASFCG
GALEPMPTEE	DEADDTSASI	ISDLICQGAQ	LGARTDRTGE	TALHLAARYA
RADAAKRLLD	AGADTNAQDH	SGRTPLHTAV	TADAQGVFQI	LIRNRSTDLD
ARMADGSTAL	ILAARLAVEG	MVEELIASHA	DVNAVDELGK	SALHWAAAVN
NVEATLALLK	NGANKDMQDS	KEETPLFLAA	REGSYEAAKL	LLDHFANREI
TDHLDRLPRD	VAQERLHQDI	VRLLDQPSGP	RSPPGPHGLG	PLLCPPGAFL
PGLKAAQSGS	KKSRRPPGKA	GLGPQGPRGR	GKKLTLACPG	PLADSSVTLS
PVDSLDSPRP	FGGPPASPGG	FPLEGPYAAA	TATAVSLAQL	GGPGRAGLGR
QPPGGCVLSL	GLLNPVAVPL	DWARLPPPAP	PGPSFLLPLA	PGPQLLNPGT
PVSPQERPPP	YLAVPGHGEE	YPAAGAHSSP	PKARFLRVPS	EHPYLTPSPE
SPEHWASPSP	PSLSDWSEST	PSPATATGAM	ATTTGALPAQ	PLPLSVPSSL
AQAQTQLGPQ	PEVTPKRQVL	A

Funkcija

Ovaj gen kodira treći otkriveni ljudski homolog membranskog proteina tipa zareznih proteina. Drosophila melanogaster. U rodu Drosophila, interakcija zareza sa njegovim ćelijski vezanim ligandima (delta, serata) uspostavlja međućelijski signalni put koji ima ključnu ulogu u razvoju neurona. Homolozi zareznog-liganda su također identificirani kod ljudi, ali treba precizno utvrditi interakcije između ovih liganada i homologa ljudskog zareznog proteina.

Patologija

Mikrografija CADASIL-a sa zarezom 3, imunoboja.

Mutacije u NOTCH3 identificirane su kao osnovni uzrok cerebralne autosomno dominantne arteriopatije, sa subkortikalnim infarktom i leukoencefalopatijom (CADASIL).^[6] Mutacije u NOTCH3 također su identificirane u porodicama s Alzheimerovom bolešću.^[7] Odrasli nokaut-miševi Notch3 pokazuju nepotpuno sazrijevanje neurona u leđnom rogu kičmene moždine, što rezultira trajno povećanom nociceptivnom osjetljivošću.^[8]

Mutacije u NOTCH3 povezane su sa sindromom lateralne meningokele.^[9]

Farmaceutski cilj

Notch3 se istražuje kao meta za lijekove protiv raka, jer je prekomjerno izražen u nekoliko tipova karcinoma.^[10] Rana klinička ispitivanja Pfizer-ovog PF-06650808, antitela protiv Notch3 povezanog sa citotoksičnim lijekom, pokazala su efikasnost protiv solidnih tumora.^[11]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000074181 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000038146 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (15. 9. 1994). "Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3". Genomics. 23 (2): 408–19. doi:10.1006/geno.1994.1517. PMID 7835890.
^ ^a ^b "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)".
^ Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, Dursun B, Bilgic B, Santana I, Hanagasi H, Gurvit H, Gibbs JR, Oliveira C, Emre M, Singleton A (2012). "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease". Neurobiol. Aging. 33 (5): 1008.e17–23. doi:10.1016/j.neurobiolaging.2011.10.009. PMC 3306507. PMID 22153900.
^ Rusanescu G, Mao J (2014). "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". J. Cell. Mol. Med. 18 (10): 2103–16. doi:10.1111/jcmm.12362. PMC 4244024. PMID 25164209.
^ Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K (2014). "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". Am. J. Med. Genet. A. 167A (2): 271–81. doi:10.1002/ajmg.a.36863. PMC 5589071. PMID 25394726.
^ Purow, B (2012). "Notch Inhibition as a Promising New Approach to Cancer Therapy". Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology. 727. str. 305–319. doi:10.1007/978-1-4614-0899-4_23. ISBN 978-1-4614-0898-7. PMC 3361718. PMID 22399357.
^ http://adcreview.com/pfizer-adc-development-overview-2016/

Dopunska literatura

Lewis J (1996). "Neurogenic genes and vertebrate neurogenesis". Curr. Opin. Neurobiol. 6 (1): 3–10. doi:10.1016/S0959-4388(96)80002-X. PMID 8794055. S2CID 2921624.
Joutel A, Tournier-Lasserve E (2002). "[Molecular basis and physiopathogenic mechanisms of CADASIL: a model of small vessel diseases of the brain]". J. Soc. Biol. 196 (1): 109–15. doi:10.1051/jbio/2002196010109. PMID 12134625.
Guidetti D, Casali B, Mazzei RL, Dotti MT (2006). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy". Clin. Exp. Hypertens. 28 (3–4): 271–7. doi:10.1080/10641960600549223. PMID 16833034. S2CID 360190.
Beleil OM, Mickey MR, Terasaki PI (1972). "Comparison of male and female kidney transplant survival rates". Transplantation. 13 (5): 493–500. doi:10.1097/00007890-197205000-00008. PMID 4557798. S2CID 32855236.
Larsson C, Lardelli M, White I, Lendahl U (1994). "The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation". Genomics. 24 (2): 253–8. doi:10.1006/geno.1994.1613. PMID 7698746.
Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J (1993). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12". Nat. Genet. 3 (3): 256–9. doi:10.1038/ng0393-256. PMID 8485581. S2CID 13031278.
Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996). "Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia". Nature. 383 (6602): 707–10. Bibcode:1996Natur.383..707J. doi:10.1038/383707a0. PMID 8878478. S2CID 4351873.
Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E (1997). "Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients". Lancet. 350 (9090): 1511–5. doi:10.1016/S0140-6736(97)08083-5. PMID 9388399. S2CID 38044421.
Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S (1999). "Human ligands of the Notch receptor". Am. J. Pathol. 154 (3): 785–94. doi:10.1016/S0002-9440(10)65325-4. PMC 1866435. PMID 10079256.
Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E (2000). "The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients". J. Clin. Invest. 105 (5): 597–605. doi:10.1172/JCI8047. PMC 289174. PMID 10712431.
Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG (2000). "De novo mutation in the Notch3 gene causing CADASIL". Ann. Neurol. 47 (3): 388–91. doi:10.1002/1531-8249(200003)47:3<388::AID-ANA19>3.0.CO;2-Q. PMID 10716263.
Joutel A, Chabriat H, Vahedi K, Domenga V, Vayssière C, Ruchoux MM, Lucas C, Leys D, Bousser MG, Tournier-Lasserve E (2000). "Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL". Neurology. 54 (9): 1874–5. doi:10.1212/wnl.54.9.1874. PMID 10802807. S2CID 19374887.
Shimizu K, Chiba S, Saito T, Kumano K, Hirai H (2000). "Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors". Biochem. Biophys. Res. Commun. 276 (1): 385–9. doi:10.1006/bbrc.2000.3469. PMID 11006133.
Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD (2000). "MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors". Nat. Genet. 26 (4): 484–9. doi:10.1038/82644. PMID 11101851. S2CID 23335042.
Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (2001). "The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity". Mech. Dev. 104 (1–2): 3–20. doi:10.1016/S0925-4773(01)00373-2. PMID 11404076. S2CID 9526831.
Saxena MT, Schroeter EH, Mumm JS, Kopan R (2001). "Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis". J. Biol. Chem. 276 (43): 40268–73. doi:10.1074/jbc.M107234200. PMID 11518718.
Oliveri RL, Muglia M, De Stefano N, Mazzei R, Labate A, Conforti FL, Patitucci A, Gabriele AL, Tagarelli G, Magariello A, Zappia M, Gambardella A, Federico A, Quattrone A (2001). "A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings". Arch. Neurol. 58 (9): 1418–22. doi:10.1001/archneur.58.9.1418. PMID 11559313.
Dichgans M, Herzog J, Gasser T (2001). "NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL". Neurology. 57 (9): 1714–7. doi:10.1212/wnl.57.9.1714. PMID 11706120. S2CID 21180235.

Vanjski linkovi

NOTCH3 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000074181 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000038146 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid7835890-5] Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (15. 9. 1994). "Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3". Genomics. 23 (2): 408–19. doi:10.1006/geno.1994.1517. PMID 7835890.

[entrez-6] "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)".

[pmid22153900-7] Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, Dursun B, Bilgic B, Santana I, Hanagasi H, Gurvit H, Gibbs JR, Oliveira C, Emre M, Singleton A (2012). "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease". Neurobiol. Aging. 33 (5): 1008.e17–23. doi:10.1016/j.neurobiolaging.2011.10.009. PMC 3306507. PMID 22153900.

[pmid25164209-8] Rusanescu G, Mao J (2014). "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". J. Cell. Mol. Med. 18 (10): 2103–16. doi:10.1111/jcmm.12362. PMC 4244024. PMID 25164209.

[9] Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K (2014). "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". Am. J. Med. Genet. A. 167A (2): 271–81. doi:10.1002/ajmg.a.36863. PMC 5589071. PMID 25394726.

[10] Purow, B (2012). "Notch Inhibition as a Promising New Approach to Cancer Therapy". Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology. 727. str. 305–319. doi:10.1007/978-1-4614-0899-4_23. ISBN 978-1-4614-0898-7. PMC 3361718. PMID 22399357.

[11] ttp://adcreview.com/pfizer-adc-development-overview-2016/

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