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Methotrexate and Triptolide regulate Notch signaling pathway by targeting the Nedd4-Numb axis
Qiuyu Wu1, Xiangjie Chen1, Caixia Qiao1
1Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China.
International Immunopharmacology
|January 26, 2023
Summary
Methotrexate (MTX) suppresses the Notch signaling pathway by stabilizing Numb proteins, potentially causing myelosuppression. Triptolide may alleviate this MTX side effect.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Methotrexate (MTX) treats various conditions but can cause myelosuppression.
- The Notch signaling pathway is crucial for hematopoietic stem cell (HSC) function.
- The mechanism of MTX-induced myelosuppression and its effect on Notch signaling are unknown.
Purpose of the Study:
- To investigate if MTX affects the Notch signaling pathway.
- To elucidate the molecular mechanism underlying MTX's impact on Notch signaling.
- To explore potential interventions for MTX-induced myelosuppression.
Main Methods:
- Investigated the interaction between Nedd4 and Numb in the presence of MTX.
- Assessed the ubiquitylation and protein levels of Numb.
- Measured Notch1 protein levels.
- Evaluated the effect of Triptolide on MTX-mediated Notch signaling inhibition.
Main Results:
- MTX inhibits the interaction between Nedd4 and Numb.
- MTX restricts K48-linked polyubiquitination of Numb, leading to Numb protein stabilization.
- MTX reduces Notch1 protein levels, indicating suppression of the Notch signaling pathway.
- Triptolide alleviates the inhibitory effect of MTX on Notch signaling.
Conclusions:
- MTX suppresses the Notch signaling pathway by stabilizing Numb via Nedd4 inhibition.
- This mechanism offers insight into MTX-induced myelosuppression.
- Triptolide shows potential in mitigating MTX's adverse effects on hematopoiesis.
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