JAG1 and Associated Diseases
As an expert in the field of gene therapy research, Creative Biolabs has accumulated extensive experience. We are pleased to share professional background knowledge, such as a brief introduction to the jagged canonical Notch ligand 1 (JAG1) gene.
Overview of JAG1
The JAG1 gene is composed of 26 exons and encodes a protein of 1218 amino acids. JAG1 consists of an intracellular structure, a transmembrane domain as well as an extracellular component. As one of the common ligands, JAG1 is correlated with Notch signaling, which is critical for cellular life activities. Although this pathway was originally considered to play a major role in neurogenesis, it has now been proven to be relevant to the development of various tissues, including the heart, kidneys, and lungs.
Fig.1 Function of JAG1. (Li, 2021)
JAG1 and Associated Diseases
JAG1 is one of the ligands of Notch signaling, a well-known stem cell pathway. What's more, JAG1 also participates in many physiological and pathological processes, therefore, JAG1 mutations are related to a variety of diseases.
- Alagille syndrome (ALGS)
ALGS is a dominant genetic disorder that primarily affects the development of multiple organs, such as the heart, kidneys, liver, and vertebrae. Most cases of ALGS result from mutations in the JAG1 gene. Up to now, more than 440 JAG1 gene mutations have been detected in ALGS patients.
- Tetralogy of Fallot (TOF)
TOF is a complex congenital heart disease characterized by right ventricular outflow tract obstruction, aortic dextrorotation, and right ventricular hypertrophy. Variations in the JAG1 gene contribute to the etiology of TOF.
- Cancer
JAG1 is closely associated with many cancers. The role of JAG1 in human cancer was demonstrated in breast cancer for the first time. Furthermore, upregulation of JAG1 in adrenocortical carcinoma has been shown to enhance cancer invasion by activating the Notch pathway. In addition to breast and adrenocortical cancers, JAG1 also plays a role in cervical, prostate, gastric, liver, lung, and kidney cancers. More importantly, JAG1 has also been reported to be involved in diverse forms of leukemia and lymphoma. Currently, targeting JAG1 is considered to be a promising strategy for cancer therapy.
Potential Mechanisms
The canonical JAG1/Notch interaction results in the transport of the Notch intracellular domain into the nucleus, where it functions to activate downstream transcription of target genes. The JAG1 mutation spectrum in ALGS includes whole-gene deletions, as well as other protein-truncating mutations, including nonsense, frameshift, and missense mutations. In some cases, missense mutations are pathogenic since they are not properly transported to the cell membrane. Additionally, aberrant activation of Notch plays an oncogenic role in cancer occurrence as the JAG1/Notch cascade and activates many oncogenic factors that regulate cellular function.
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Reference
- Li, J.; et al. MicroRNA-489-3p represses hepatic stellate cells activation by negatively regulating the JAG1/Notch3 signaling pathway. Digestive Diseases and Sciences. 2021, 66(1): 143-150.
