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- Title
Annexin A2 Stabilizes Oncogenic JAG1 Intracellular Domain by Inhibiting Proteasomal Degradation in Glioblastoma Cells.
- Authors
Ham, Seok Won; Kim, Jung Yun; Seo, Sunyoung; Hong, Nayoung; Park, Min Ji; Kim, Yoonji; Jang, Junseok; Park, Sehyeon; Lee, Silvee Jisoo; Kim, Jun-Kyum; Kim, Eun-Jung; Kim, Sung-Ok; Kim, Sung-Chan; Park, Jong-Whi; Kim, Hyunggee
- Abstract
Glioblastoma (GBM) is the most lethal brain cancer, causing inevitable deaths of patients owing to frequent relapses of cancer stem cells (CSCs). The significance of the NOTCH signaling pathway in CSCs has been well recognized; however, there is no NOTCH-selective treatment applicable to patients with GBM. We recently reported that Jagged1 (JAG1), a NOTCH ligand, drives a NOTCH receptor-independent signaling pathway via JAG1 intracellular domain (JICD1) as a crucial signal that renders CSC properties. Therefore, mechanisms regulating the JICD1 signaling pathway should be elucidated to further develop a selective therapeutic regimen. Here, we identified annexin A2 (ANXA2) as an essential modulator to stabilize intrinsically disordered JICD1. The binding of ANXA2 to JICD1 prevents the proteasomal degradation of JICD1 by heat shock protein-70/90 and carboxy-terminus of Hsc70 interacting protein E3 ligase. Furthermore, JICD1-driven propagation and tumor aggressiveness were inhibited by ANXA2 knockdown. Taken together, our findings show that ANXA2 maintains the function of the NOTCH receptor-independent JICD1 signaling pathway by stabilizing JICD1, and the targeted suppression of JICD1-driven CSC properties can be achieved by blocking its interaction with ANXA2.
- Subjects
NOTCH signaling pathway; GLIOBLASTOMA multiforme; CANCER stem cells; HEAT shock proteins; UBIQUITIN ligases; CANCER relapse; ANNEXINS
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 19, p14776
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms241914776