Jagged1 (JAG1): Structure, Expression, and Disease Associations

Overview

Journal Gene

Specialty Molecular Biology

Date 2015 Nov 10

PMID 26548814

Citations 57

Authors

Christopher M Grochowski

Kathleen M Loomes

Nancy B Spinner

Affiliations

Soon will be listed here.

Abstract

Jagged1 (JAG1) is one of the 5 cell surface ligands that functions primarily in the highly conserved Notch signaling pathway. Notch signaling plays a critical role in cellular fate determination and is active throughout development and across many organ systems. The classic JAG1-NOTCH interaction leads to a cascade of proteolytic cleavages resulting in the NOTCH intracellular domain being transported into the nucleus where it functions to activate downstream transcription of target genes. JAG1 mutations have been associated with several disorders including the multi-system dominant disorder Alagille syndrome, and some cases of tetralogy of Fallot (although these may represent variable expressivity of Alagille syndrome). In addition, variations in JAG1 have been found to be associated with multiple types of cancer including breast cancer and adrenocortical carcinoma. Alagille syndrome, which primarily affects the liver, heart, skeleton, eye, face, kidney and vasculature is caused by loss of function mutations in JAG1, demonstrating that haploinsufficiency for JAG1 is disease causing, at least in these tissues. Expression and conditional gene knockout studies of JAG1 (Jag1) have correlated with tissue-specific disease phenotypes and have provided insight into both disease pathogenesis and human development.

Citing Articles

The Role of Visual Electrophysiology in Systemic Hereditary Syndromes.

Yu M, Vieta-Ferrer E, Bakdalieh A, Tsai T Int J Mol Sci. 2025; 26(3).

PMID: 39940729 PMC: 11816691. DOI: 10.3390/ijms26030957.

Salidroside Prevents Keloid Fibroblast Aggressive Progression by Upregulating miR-26a-5p to Inhibit JAG1.

Qin Y, Zhang R, Liu W, Xu X, Chen F Cell Biochem Biophys. 2025; .

PMID: 39825059 DOI: 10.1007/s12013-025-01667-9.

Damage of the Bone Marrow Stromal Precursors in Patients with Acute Leukemia at the Onset of the Disease and During Treatment.

Sadovskaya A, Petinati N, Shipounova I, Drize N, Smirnov I, Pobeguts O Int J Mol Sci. 2025; 25(24.

PMID: 39769050 PMC: 11677965. DOI: 10.3390/ijms252413285.

JAG1 mediates apoptosis in herpes simplex keratitis by suppressing autophagy via ROS/JAG1/NOTCH1/pULK1 signaling pathway.

Chang J, Yao Y, Sun X, Wang W, Qian H, Liu Y Cell Biol Toxicol. 2024; 41(1):1.

PMID: 39704867 PMC: 11662045. DOI: 10.1007/s10565-024-09968-0.

Convergent Degenerated Regulatory Elements Associated with Limb Loss in Limbless Amphibians and Reptiles.

Zhu C, Li S, Zhang D, Zhang J, Wang G, Zhou B Mol Biol Evol. 2024; 41(11).

PMID: 39530343 PMC: 11600591. DOI: 10.1093/molbev/msae239.

References

Hofmann J, Zovein A, Koh H, Radtke F, Weinmaster G, Iruela-Arispe M . Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development. 2010; 137(23):4061-72. PMC: 2976287. DOI: 10.1242/dev.052118. View

Ellisen L, Bird J, West D, Soreng A, Reynolds T, Smith S . TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991; 66(4):649-61. DOI: 10.1016/0092-8674(91)90111-b. View

McDaniell R, Warthen D, Sanchez-Lara P, Pai A, Krantz I, Piccoli D . NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006; 79(1):169-73. PMC: 1474136. DOI: 10.1086/505332. View

Shimizu K, Chiba S, Saito T, Kumano K, Hirai H . Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors. Biochem Biophys Res Commun. 2000; 276(1):385-9. DOI: 10.1006/bbrc.2000.3469. View

Adam J, Myat A, le Roux I, Eddison M, Henrique D, Ish-Horowicz D . Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development. Development. 1998; 125(23):4645-54. DOI: 10.1242/dev.125.23.4645. View

Turnpenny P, Ellard S . Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2011; 20(3):251-7. PMC: 3283172. DOI: 10.1038/ejhg.2011.181. View

Morrissette J, Colliton R, Spinner N . Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet. 2001; 10(4):405-13. DOI: 10.1093/hmg/10.4.405. View

Dickson B, Mulligan A, Zhang H, Lockwood G, OMalley F, Egan S . High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Mod Pathol. 2007; 20(6):685-93. DOI: 10.1038/modpathol.3800785. View

Li D, Masiero M, Banham A, Harris A . The notch ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol. 2014; 4:254. PMC: 4174884. DOI: 10.3389/fonc.2014.00254. View

10.

Loomes K, Russo P, Ryan M, Nelson A, Underkoffler L, Glover C . Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology. 2007; 45(2):323-30. DOI: 10.1002/hep.21460. View

11.

Krantz I, Piccoli D, Spinner N . Alagille syndrome. J Med Genet. 1997; 34(2):152-7. PMC: 1050871. DOI: 10.1136/jmg.34.2.152. View

12.

Cheng H, Kopan R . The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int. 2005; 68(5):1951-2. DOI: 10.1111/j.1523-1755.2005.00627.x. View

13.

Lindsell C, Shawber C, Boulter J, Weinmaster G . Jagged: a mammalian ligand that activates Notch1. Cell. 1995; 80(6):909-17. DOI: 10.1016/0092-8674(95)90294-5. View

14.

Jones E, Clement-Jones M, Wilson D . JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype. J Med Genet. 2000; 37(9):658-62. PMC: 1734694. DOI: 10.1136/jmg.37.9.658. View

15.

Chillakuri C, Sheppard D, Lea S, Handford P . Notch receptor-ligand binding and activation: insights from molecular studies. Semin Cell Dev Biol. 2012; 23(4):421-8. PMC: 3415683. DOI: 10.1016/j.semcdb.2012.01.009. View

16.

Loomes K, Underkoffler L, Morabito J, Gottlieb S, Piccoli D, Spinner N . The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome. Hum Mol Genet. 1999; 8(13):2443-9. DOI: 10.1093/hmg/8.13.2443. View

17.

McCright B, Lozier J, Gridley T . A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 2002; 129(4):1075-82. DOI: 10.1242/dev.129.4.1075. View

18.

Xue Y, Gao X, Lindsell C, Norton C, Chang B, Hicks C . Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet. 1999; 8(5):723-30. DOI: 10.1093/hmg/8.5.723. View

19.

Artavanis-Tsakonas S, Rand M, Lake R . Notch signaling: cell fate control and signal integration in development. Science. 1999; 284(5415):770-6. DOI: 10.1126/science.284.5415.770. View

20.

Crosnier C, Attie-Bitach T, Encha-Razavi F, Audollent S, Soudy F, Hadchouel M . JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology. 2000; 32(3):574-81. DOI: 10.1053/jhep.2000.16600. View