Annexin A2 Stabilizes Oncogenic JAG1 Intracellular Domain by Inhibiting Proteasomal Degradation in Glioblastoma Cells

Seok Won Ham, Jung Yun Kim, Sunyoung Seo, Nayoung Hong, Min Ji Park, Yoonji Kim, Junseok Jang, Sehyeon Park, Silvee Jisoo Lee, Jun Kyum Kim, Eun Jung Kim, Sung Ok Kim, Sung Chan Kim, Jong Whi Park, Hyunggee Kim

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number14776
JournalInternational journal of molecular sciences
Volume24
Issue number19
DOIs
Publication statusPublished - 2023 Oct

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • ANXA2
  • cancer stem cell
  • Glioblastoma
  • JAG1
  • JICD1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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