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)[1] Bend 19p13.12 Početak 15,159,038 bp[1] Kraj 15,200,995 bp[1]
Lokacija gena (miš) Hrom. Hromosom 17 (miš)[2] Bend 17 B1|17 17.37 cM Početak 32,339,794 bp[2] Kraj 32,385,826 bp[2]
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
Vrste	Čovjek	Miš
Entrez	4854	18131
Ensembl	ENSG00000074181	ENSMUSG00000038146
UniProt	Q9UM47	Q61982
RefSeq (mRNK)	NM_000435	NM_008716
RefSeq (bjelančevina)	NP_000426	NP_032742
Lokacija (UCSC)	Chr 19: 15.16 – 15.2 Mb	Chr 17: 32.34 – 32.39 Mb
PubMed pretraga	[3]	[4]
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

1. GRCh38: Ensembl release 89: ENSG00000074181 - Ensembl, maj 2017
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.
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.
6. "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)".
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.
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. http://adcreview.com/pfizer-adc-development-overview-2016/

Dopunska literatura

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• 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.
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• 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)