JAG2 and Associated Diseases
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Overview of JAG2
Jagged canonical notch ligand 2 (JAG2, also known as Jagged 2) is a protein encoded by JAG2 in humans. JAG2 plays important role in the notch signaling pathway, which involves in regulation of intercellular signaling during proper embryonic development and cell fate decisions. JAG2 is one of the ligands that can activate notch and related receptors. It is reported that JAG2 can interact with NOTCH2. Until now, two transcript variants of JAG2 have been reported.
JAG2 in Disease
Diseases associated with JAG2 include muscular dystrophy, limb-girdle, and cancer such as colorectal cancer.
- Muscular dystrophy
Pathogenic variants in JAG2 are associated with muscular dystrophy (MD). The conserved Notch signaling pathway is important to the development and homeostasis of multiple tissues such as skeletal muscle. According to whole-exome sequencing, different kinds of JAG2 variants are identified in MD patients such as missense variants and nonsense variants. In patients, downregulated JAG2 induces the decreased expression of multiple members of the Notch pathway in myoblasts. According to the in silico analysis, many JAG2 missense variants are predicted to be associated with structural changes and protein misfolding. In summary, pathogenic variants in JAG2 suggest that notch pathway dysfunction is a disease mechanism of MD.
- Colorectal cancer
JAG2 can be regarded as a new target for the treatment of colorectal cancer (CRC). According to recent studies, the notch signaling pathway plays an important role in the development of CRC. As a member of notch ligands, upregulated expression of JAG2 is found in intestinal tumors compared with nearby normal mucosa. In a panel of human CRC cell lines, ectopic expression of JAG2 can be observed, too. Knockdown of β-catenin in human CRC cell lines will decrease JAG2 expression, whereas deletion of APC gene, the inhibitor of the β-catenin signaling pathway, will increase the expression of JAG2. Knockdown or overexpression of JAG2 will decrease or increase the chemoresistance of CRC cells to the chemotherapeutic agents, respectively. Thus, JAG2 can modulate the sensitivity of CRC cells to chemotherapeutic agents.
Fig.1 Knockdown of JAG2 will reduce the chemoresistance of CRC cells to the chemotherapeutic agent Dox. (Vaish, 2017)
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References
- Coppens, S.; et al. A form of muscular dystrophy associated with pathogenic variants in JAG2. The American Journal of Human Genetics. 2021, 108; 840–856.
- Vaish, V.; et al. Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells. Oncotarget. 2017, 8: 53262–53275.
