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SorCS3 promotes the internalization of p75NTR to inhibit GBM progression
Yanqiu Zhang1, Yue Li2,3, Yuhua Fan1
1Department of Basic Medical College, Harbin Medical University (Daqing), Daqing, China.
Abstract:
Glioblastoma (GBM) is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. Previous reports showed that Sortilin related VPS10 domain containing receptor 3 (SorCS3) has the ability to regulate internalization. However, the impacts of SorCS3 on the biological processes involved in GBM have not yet been reported. In this study, we investigated the bio-function of SorCS3 in GBM. We found that SorCS3 was significantly downregulated in GBM. In addition, low expression level of SorCS3 predicted poor prognoses in patients with GBM. Here, we proved that SorCS3 suppressed cell invasion and proliferation mainly via NGF/p75NTR pathway in GBM. We found that SorCS3 co-localized with p75NTR in GBM cells and regulated the p75NTR protein level by promoting trafficking of the endosomal to the lysosome. Immunofluorescence (IF) and Co-Immunoprecipitation (Co-IP) detection confirmed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibit of glioma progression. Taken together, our work suggests that SorCS3 is a marker of promising prognosis in GBM patients and suggests that SorCS3 regulates internalization, which plays a pivotal role in inhibiting glioma progression.
Insights
Sortilin related VPS10 domain containing receptor 3 (SorCS3) is downregulated in glioblastoma (GBM). SorCS3 suppresses GBM cell invasion and proliferation by regulating the NGF/p75NTR pathway, indicating its potential as a prognostic marker.
Area of Science:
- Neuro-oncology
- Cellular signaling
- Molecular biology
Background:
- Glioblastoma (GBM) is a fatal brain cancer driven by disrupted cellular signaling.
- Internalization is crucial for maintaining signaling balance.
- Sortilin related VPS10 domain containing receptor 3 (SorCS3) is known to influence cellular internalization.
Purpose of the Study:
- To investigate the biological function and prognostic significance of SorCS3 in GBM.
- To elucidate the mechanism by which SorCS3 affects GBM progression.
Main Methods:
- Analysis of SorCS3 expression levels in GBM tissues.
- Correlation of SorCS3 expression with patient prognosis.
- Investigation of SorCS3's role in cell invasion and proliferation.
- Immunofluorescence (IF) and Co-Immunoprecipitation (Co-IP) assays to study protein interactions and localization.
- Assessment of SorCS3's effect on the NGF/p75NTR pathway.
Main Results:
- SorCS3 expression is significantly downregulated in GBM.
- Low SorCS3 expression correlates with poor prognosis in GBM patients.
- SorCS3 suppresses GBM cell invasion and proliferation.
- SorCS3 interacts with p75NTR, promoting its internalization and lysosomal degradation via the NGF/p75NTR pathway.
Conclusions:
- SorCS3 acts as a tumor suppressor in GBM.
- SorCS3's downregulation is linked to adverse outcomes in GBM patients.
- SorCS3 regulates internalization of p75NTR, offering a potential therapeutic target for inhibiting glioma progression.
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