JAG1

JAG1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2KB9, 2VJ2, 4CBZ, 4CC0, 4CC1, 4XI7, 5BO1
Identifikatori
Aliasi	JAG1
Vanjski ID-jevi	OMIM: 601920 MGI: 1095416 HomoloGene: 180 GeneCards: JAG1
Lokacija gena (čovjek)
Hrom.	Hromosom 20 (čovjek)
Kraj	10,673,999 bp
Lokacija gena (miš)
Hrom.	Hromosom 2 (miš)
Kraj	136,958,564 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• calcium ion binding; • structural molecule activity; • Notch binding; • GO:0001948, GO:0016582 vezivanje za proteine; • growth factor activity; • phospholipid binding;
Ćelijska komponenta	• integral component of membrane; • adherens junction; • ćelijska membrana; • apical part of cell; • integral component of plasma membrane; • extracellular region; • apical plasma membrane; • membrana;
Biološki proces	• Notch signaling pathway; • T cell mediated immunity; • negative regulation of fat cell differentiation; • pulmonary valve morphogenesis; • glomerular visceral epithelial cell development; • endocardial cushion cell development; • loop of Henle development; • negative regulation of neuron differentiation; • distal tubule development; • pulmonary artery morphogenesis; • cardiac septum morphogenesis; • negative regulation of cell differentiation; • response to muramyl dipeptide; • ciliary body morphogenesis; • aorta morphogenesis; • nervous system development; • keratinocyte differentiation; • cardiac neural crest cell development involved in outflow tract morphogenesis; • neuronal stem cell population maintenance; • negative regulation of stem cell differentiation; • multicellular organism development; • cell communication; • blood vessel remodeling; • inner ear auditory receptor cell differentiation; • positive regulation of osteoblast differentiation; • regulation of cell population proliferation; • Angiogeneza; • nephron development; • animal organ morphogenesis; • cell fate determination; • inner ear development; • endothelial cell differentiation; • camera-type eye development; • myoblast differentiation; • cardiac right ventricle morphogenesis; • morphogenesis of an epithelial sheet; • positive regulation of myeloid cell differentiation; • positive regulation of Notch signaling pathway; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • Notch signaling involved in heart development; • negative regulation of endothelial cell differentiation; • regulation of signaling receptor activity; • negative regulation of cell-matrix adhesion; • negative regulation of cell-cell adhesion; • negative regulation of cell migration; • Hematopoeza; • aortic valve morphogenesis; • cardiac epithelial to mesenchymal transition; • positive regulation of cardiac epithelial to mesenchymal transition; • negative regulation of Notch signaling pathway;
	Izvori:Amigo / QuickGO
Ortolozi
	182
	16449
	ENSG00000101384
	ENSMUSG00000027276
	P78504
	Q9QXX0
	NM_000214
	NM_013822
	NP_000205
	NP_038850
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Nazubljeni zarezni protein 1 (JAG1) jest jedan od pet površinskih proteina ćelija (liganda), koji stupaju u interakciju sa četiri receptora na putu sisarske zarezne signalizacije. Signalni zarezni put je visoko konzervirani put koji funkcionira za uspostavljanje i regulaciju odluka o sudbini ćelija u mnogim organskim sistemima. Kada se dese interakcije JAG1-NOTCH (receptor-ligand), aktivira se kaskada proteolitskog cijepanja što rezultira aktivacijom transkripcije za ciljne nizvodne gene. Smješten na ljudskom hromosomu 20, gen JAG1 eksprimiran je u više organskih sistema u tijelu i uzrokuje autosomno dominantni poremećaj Alagilleov sindrom (ALGS) koji je rezultat gubitka funkcije mutacije unutar gena. JAG1 je takođe označen kao CD339 (klaster diferencijacije 339).

Struktura i funkcija

JAG1 je prvi put identificiran kao ligand koji je bio u stanju da aktivira zarezne receptore kada je kloniran u pacova 1995. godine.^[5] Nalazi se na citogenetičkoj poziciji 20p12.2 i genomskoj lokaciji (GRCh37) chr20:10,618,331-10,654,693 on the human chromosome 20.^[6] Struktura proteina JAG1 uključuje malu unutarćelijsku komponentu, transmembranski motiv, a nastavlja se vanćelijskom regijom koja sadrži sekvencu bogatu cisteinom, 16 ponavljanja sličnih EGF-u, DSL domen, i na kraju signalni peptid u ukupnoj dužini od 1.218 aminokiselina koje kodira preko 26 egzona.^[7]

Protein JAG1 kodiran sa JAG1, ljudski je homolog nazubljenog proteina u rodu Drosophila.^[5] Ljudski JAG1 jedan je od pet liganada za receptore u signalnom putu NOTCH koji pomaže u određivanju ćelijske sudbine i aktivan je u mnogim razvojnim fazama. Vanćelijska komponenta proteina JAG1 fizički komunicira sa svojim odgovarajućim zareznim (Notch) receptorima. Ova interakcija pokreće kaskadu proteolitskog cijepanja, što dovodi do toga da se izvorni NOTCH unutarćelijsi domen prebaci u ćelijsko jedro, što dovodi do aktivacije različitih ciljnih gena.^[8]^[9]^[10]^[11]

Aminokiselinska sekvenca

MRSPRTRGRSGRPLSLLLALLCALRAKVCGASGQFELEILSMQNVNGELQ NGNCCGGARNPGDRKCTRDECDTYFKVCLKEYQSRVTAGGPCSFGSGSTP VIGGNTFNLKASRGNDRNRIVLPFSFAWPRSYTLLVEAWDSSNDTVQPDS IIEKASHSGMINPSRQWQTLKQNTGVAHFEYQIRVTCDDYYYGFGCNKFC RPRDDFFGHYACDQNGNKTCMEGWMGPECNRAICRQGCSPKHGSCKLPGD CRCQYGWQGLYCDKCIPHPGCVHGICNEPWQCLCETNWGGQLCDKDLNYC GTHQPCLNGGTCSNTGPDKYQCSCPEGYSGPNCEIAEHACLSDPCHNRGS CKETSLGFECECSPGWTGPTCSTNIDDCSPNNCSHGGTCQDLVNGFKCVC PPQWTGKTCQLDANECEAKPCVNAKSCKNLIASYYCDCLPGWMGQNCDIN INDCLGQCQNDASCRDLVNGYRCICPPGYAGDHCERDIDECASNPCLNGG HCQNEINRFQCLCPTGFSGNLCQLDIDYCEPNPCQNGAQCYNRASDYFCK CPEDYEGKNCSHLKDHCRTTPCEVIDSCTVAMASNDTPEGVRYISSNVCG PHGKCKSQSGGKFTCDCNKGFTGTYCHENINDCESNPCRNGGTCIDGVNS YKCICSDGWEGAYCETNINDCSQNPCHNGGTCRDLVNDFYCDCKNGWKGK TCHSRDSQCDEATCNNGGTCYDEGDAFKCMCPGGWEGTTCNIARNSSCLP NPCHNGGTCVVNGESFTCVCKEGWEGPICAQNTNDCSPHPCYNSGTCVDG DNWYRCECAPGFAGPDCRININECQSSPCAFGATCVDEINGYRCVCPPGH SGAKCQEVSGRPCITMGSVIPDGAKWDDDCNTCQCLNGRIACSKVWCGPR PCLLHKGHSECPSGQSCIPILDDQCFVHPCTGVGECRSSSLQPVKTKCTS DSYYQDNCANITFTFNKEMMSPGLTTEHICSELRNLNILKNVSAEYSIYI ACEPSPSANNEIHVAISAEDIRDDGNPIKEITDKIIDLVSKRDGNSSLIA AVAEVRVQRRPLKNRTDFLVPLLSSVLTVAWICCLVTAFYWCLRKRRKPG SHTHSASEDNTTNNVREQLNQIKNPIEKHGANTVPIKDYENKNSKMSKIR THNSEVEEDDMDKHQQKARFAKQPAYTLVDREEKPPNGTPTKHPNWTNKQ DNRDLESAQSLNRMEYIV

O: Alanin 

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 

P: Glutamin 

R: Arginin 

S: Serin 

T: Treonin 

V: Valin 

W: Triptofan 

Y: Tirozin

Profil ekspresije i studije miša

Studije fkuorescentne hibridizacije in situ i uslovnog nokautiranja gena pomogle su da se demonstrira uloga „JAG1“ u razvoju i njeni efekti na različite organske sisteme. Kod ljudi, JAG1 ima široku ekspresiju u mnogim tipovima tkiva, uključujući pankreas, srce, placentu, prostatu, pluća, bubrege, timus, testise i leukocite kod odraslih osoba.^[12] U razvijajućen embrionu u ekspresija JAG1 koncentrirana je oko plućne arterije, mezokarda, distalnog kardiološkog odvodnog trakta, glavnih arterija, metanefrosa, granatih lukova, pankreasa, portne vene i otocista.^[12] Općenito, obrasci ekspresije JAG1 koreliraju sa organskim sistemima pogođenim ALGS-om, iako je važno napomenuti da svi+a tkiva u kojima se eksprimira JAG1 ne utiču na ALGS. U novije vrijeme utvrđeno je da je ekspresija JAG1 promijenjena kod pacijenata sa rakom dojke i adrenokorteksnim karcinomom.^[13]^[14]

Modeli miša kod kojih je (recesivni) gen Jag1 isključen u određenim tkivima (uslovni nokaut modeli miša) korišteni su za proučavanje uloge Jag1 u mnogim područjima specifičnim za tkivo. Iako se pokazalo da su homozigotne delecije Jag1 smrtonosne kod embriona miševa, a heterozigotne delecije mogu pokazati samo ograničeni fenotip (uključujući oko); haploinsuficijentni miševi za oba Jag1 i Notch2 prisutni su s ALGS fenotipom.^[15] Uvjetno nokautiranje gena u modelima miša s Jag1 mutacijama usmjerenim na portnu venu , mezenhim, endotel i kranijskii nervni greben svi pokazuju karakteristike klasične ekspresije onima kod osoba s ALGS-om, ističući ulogu ovog tkiva u porijeklu bolesti ^[16]^[17]^[18]^[19]^[20]

Fenotip bolesti

ALGS je autosomno dominantni multi-sistemski poremećaj koji pogađa nekoliko tjelesnih sistema, uključujući jetru, srce, skelet, oko, strukturu lica, bubrege i vaskularni sistem. Klinički najvažnije zabrinutosti proizlaze iz problema sa jetrom, srcem, cirkulacijskim sistemima ili bubrezima. Prvo je otkriveno da su mutacije u JAG1 odgovorne za ALGS, u i Dječijoj bolnici u Filadelfiji i Nacionalnom institutu za zdravstvo, 1997.^[6] Pacijenti koji su klinički u skladu s poremećajem obično imaju mutaciju u JAG1 (94%), dok 2% imaju mutaciju u NOTCH2.^[21] Preko polovine osoba sa mutacijama u genu nije ga naslijedilo ni od jednog roditelja, pa tako ima mutaciju de novo.^[21]^[22] Tipovi mutacija JAG1 uključuju skraćivanje bjelančevina (mjesto prerade, pomicanje okvira i nonsens, misens mutacije i delecije cijelih gena, što čini 80%, odnosno 7%, i 12%. Budući da svi tipovi mutacija dovode do fenotipa pacijenta, smatra se da je haploinsuficijencija JAG1 vjerovatni mehanizam djelovanja bolesti.^[23]^[24]^[25]

Iako nekii mogu imati niz tipova mutacija u JAG1 , sve poznate mutacije dovode do gubitka funkcije jedne kopije i nema korelacije između tipa ili lokacije mutacije i težine bolesti. Iako osobe s ALGS imaju nekoliko pogođenih tjelesnih sistema, postoji podskup osoba s mutacijama JAG1 koje se javljaju sa Fallotovum tetralogijom/plućnom stenozom koje ne pokazuju ostale kliničke znakove sindroma.^[26] S obzirom na varijabilnu ekspresivnost bolesti, mogu biti prisutni i drugi genetički ili ekološki modifikatori izvan originalne mutacije JAG1.

U novije vrijeme promjene u izražavanju JAG1 implicirane su u mnoge vrste karcinoma. Konkretno, regulacija JAG1 korelirana je i sa lošim ukupnim stopama preživljavanja od raka dojke i sa pojačanom proliferacijom tumora kod pacijenata sa adrenokortsksnim karcinomom.^[13]^[27]^[28]^[29]

Također pogledajte

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000101384 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000027276 - 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.
^ ^a ^b Lindsell CE, Shawber CJ, Boulter J, Weinmaster G (1995). "Jagged: a mammalian ligand that activates Notch1". Cell. 80 (6): 909–17. doi:10.1016/0092-8674(95)90294-5. PMID 7697721.
^ ^a ^b Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997). "Mutations in the human Jagged1 gene are responsible for Alagille syndrome". Nat. Genet. 16 (3): 235–42. doi:10.1038/ng0797-235. PMID 9207787. S2CID 5775213.
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^ High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008). "Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development". Proc. Natl. Acad. Sci. U.S.A. 105 (6): 1955–9. Bibcode:2008PNAS..105.1955H. doi:10.1073/pnas.0709663105. PMC 2538864. PMID 18245384.
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Dopunska literatura

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Lindsell CE, Boulter J, diSibio G, Gossler A, Weinmaster G (1997). "Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development". Mol. Cell. Neurosci. 8 (1): 14–27. doi:10.1006/mcne.1996.0040. PMID 8923452. S2CID 8058790.
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Vanjski linkovi

GeneReviews/NCBI/UW/NIH entry on Alagille syndrome
OMIM entries on Alagille syndrome
JAG1 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
Alagilleov sindrom

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000101384 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000027276 - 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.

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