NF2 regulates IP3R-mediated Ca2+ signal and apoptosis in meningiomas.
FASEB J
; 38(13): e23737, 2024 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-38953724
ABSTRACT
Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Calcium
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Apoptosis
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Calcium Signaling
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Inositol 1,4,5-Trisphosphate Receptors
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Meningeal Neoplasms
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Meningioma
Limits:
Animals
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Humans
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2024
Document type:
Article
Affiliation country: