Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with four receptors in the mammalianNotch signaling pathway. The Notch signaling pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade ofproteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on humanchromosome 20, theJAG1 gene is expressed in multiple organ systems in the body and causes theautosomal dominant disorderAlagille syndrome (ALGS) resulting from loss of function mutations within the gene.JAG1 has also been designated asCD339 (cluster of differentiation 339).
JAG1 was first identified as aligand that was able to activate notch receptors when the rat geneJagged encoding a protein homolog wascloned in 1995.[5][6] The structure of the JAG1 protein includes a smallintracellular component, atransmembrane motif, proceeded by anextracellular region containing a cystine-rich region, 16EGF-like repeats, a DSL domain, and finally asignal peptide totaling 1218amino acids in length over 26 codingexons.[7]
The JAG1 protein encoded byJAG1 is the human homolog of theDrosophila jagged protein.[5] Human JAG1 is one of five ligands forreceptors in the NOTCH signaling pathway which helps to determine cellular fate and is active during many developmental stages. The extracellular component of the JAG1 protein physically interacts with its respective Notch receptor. This interaction kicks off a cascade ofproteolytic cleavages leading to the original NOTCHintracellular domain being trafficked into thenucleus of the cell leading to the activation of different target genes.[8][9][10][11]
Mouse models where the Jag1 gene is turned off in certain tissues (conditional knockout mouse models) have been used to study the role of Jag1 in many tissue specific areas. Whilehomozygous deletions of Jag1 have been shown to be embryonic lethal in mice, andheterozygous deletions may show only a limitedphenotype (involving the eye), micehaploinsufficient for both Jag1 and Notch2 present with the ALGS phenotype.[15]Conditional gene knockout mouse models with Jag1 mutations targeted to the portal veinmesenchyme,endothelium, and cranial neural crest all exhibit features classic to those in individuals with ALGS, highlighting the role of this tissue type in disease origins[16][17][18][19][20]
ALGS is anautosomal dominant multi-system disorder affecting several body systems including theliver,heart,skeleton,eye, facial structure,kidneys andvascular system. The most clinically significant concerns stem from liver, heart, vascular or renal problems. Mutations inJAG1 were first discovered to be responsible for ALGS by researchers atThe Children's Hospital of Philadelphia and theNational Institutes of Health in 1997.[6] Patients who are clinically consistent with the disorder usually have amutation inJAG1 (94%), while a smaller 2% have a mutation inNOTCH2.[21] Over half of individuals with mutations in the gene did not inherit it from either parent, and thus have ade novo mutation.[21][22]JAG1 mutation types include protein truncating (splice site,frameshift, andnonsense),missense, and whole gene deletions accounting for 80%, 7%, and 12% respectively. Since all mutation types lead to a patient phenotype, it is thought thathaploinsufficiency forJAG1 is the likely disease mechanism of action.[23][24][25] Although individuals can have a range of mutation types inJAG1, all of the known mutations lead to loss of the function of one copy, and, there is no correlation between mutation type or location and disease severity. Though individuals with ALGS have several body systems affected, there is a subset of individuals withJAG1 mutations who present withtetralogy of fallot/pulmonary stenosis that do not show the other clinical signs of the syndrome.[26] Given the variable expressivity of the disease, there may be other genetic or environmental modifiers present beyond the originalJAG1 mutation.
More recently,JAG1 expression changes have been implicated in many types of cancer. Specifically, up regulation of JAG1 has been correlated with both poor overall breast cancer survival rates and an enhancement of tumor proliferation in adrenocortical carcinoma patients.[13][27][28][29]
^McCright B, Lozier J, Gridley T (2002). "A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency".Development.129 (4):1075–82.doi:10.1242/dev.129.4.1075.PMID11861489.
^Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O, Hadchouel M, Meunier-Rotival M (1999). "Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome".Gastroenterology.116 (5):1141–8.doi:10.1016/S0016-5085(99)70017-X.PMID10220506.
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.PMID8923452.S2CID8058790.
Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB (1997). "Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1".Nat. Genet.16 (3):243–51.doi:10.1038/ng0797-243.PMID9207788.S2CID8794354.
Wong MK, Prudovsky I, Vary C, Booth C, Liaw L, Mousa S, Small D, Maciag T (2000). "A non-transmembrane form of Jagged-1 regulates the formation of matrix-dependent chord-like structures".Biochem. Biophys. Res. Commun.268 (3):853–9.doi:10.1006/bbrc.2000.2173.PMID10679295.
